Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The cytokine-activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade is a pleiotropic pathway that involves receptor subunit multimerization. The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine-threonine kinase that perceives and integrates a variety of intracellular and environmental stimuli to regulate essential activities such as cell development and metabolism. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a prototypical metabolic nuclear receptor involved in neural differentiation and axon polarity. The JAK-STAT, mTOR, and PPARγ signaling pathways serve as a highly conserved signaling hub that coordinates neuronal activity and brain development. Additionally, overactivation of JAK/STAT, mTOR, and inhibition of PPARγ signaling have been linked to various neurocomplications, including neuroinflammation, apoptosis, and oxidative stress. Emerging research suggests that even minor disruptions in these cellular and molecular processes can have significant consequences manifested as neurological and neuropsychiatric diseases. Of interest, target modulators have been proven to alleviate neuronal complications associated with acute and chronic neurological deficits. This research-based review explores the therapeutic role of JAK-STAT, mTOR, and PPARγ signaling modulators in preventing neuronal dysfunctions in preclinical and clinical investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

8-bAMP:

8-Bromo-cAMP

AD:

Alzheimer’s disease

ADPN-FGF9 pathway:

Adiponectin-fibroblast growth factor 9

ALS:

Amyotrophic lateral sclerosis

Akt:

Protein kinase B

AMPK:

AMP-activated protein kinase

AP-1:

Activator protein 1

APP:

Amyloid precursor protein

APAF-1:

Apoptotic protease activating factor

ASD:

Autism spectrum disorder

ATP:

Adenosine triphosphate

AVPR1a:

Central arginine vasopressin receptor 1A

Aβ:

Amyloid β

Bax:

Bcl-2-associated X protein

bak:

Bcl-2 homologous antagonist/killer

Bcl-2:

B cell CLL (chronic lymphocytic leukemia)/lymphoma-2

BDNF:

Brain-derived neurotrophic factor

BMP2:

Bone morphogenetic proteins

BOLD:

Blood oxygen level-dependent

CBP:

CREB binding protein

CDK5:

Cyclin-dependent kinase 5

CHRNA:

Cholinergic receptor nicotinic alpha

CHRNB2:

Cholinergic receptor nicotinic beta 2 subunit

CMS:

Chronic mild stress

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

COX2:

Cyclooxygenase 2

CREB:

CAMP-response element binding protein

CTEP:

2-Chloro-4-[2[2,5-dimethyl-1-[4-(trifluoromethoxy) phenyl] imidazol-4-yl] ethynyl] pyridine

Cx:

Cystine/glutamate exchange system

dATP:

Deoxyadenosine triphosphate

DEPDC5:

DEP domain-containing 5

DISC1:

Disrupted in schizophrenia 1

DJ-1:

Protein deglycase

EAAT2:

Excitatory amino acid transporter 2

EAE:

Experimental autoimmune encephalomyelitis

EGF:

Epidermal growth factor

EIF4EBP1:

Eukaryotic translation initiation factor 4E-binding protein 1

EPO:

Erythropoietin receptor

ERK2:

Extracellular signal-regulated kinase 2

EUG:

Eugenol

FCDs IIb:

Focal cortical dysplasias

FOXP2:

Transcription factor forkhead box P2

GABAA :

Gamma-aminobutyric acid A

GCD:

Granule cell dispersion

G-CSF:

Granulocyte colony-stimulating factor

GFAP:

Glial fibrillary acidic protein

GH:

Growth hormone

GLAST:

Glutamate aspartate transporter

Glu R:

Glutamate receptors

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

Gpx:

Glutathione peroxidase

GSH:

Glutathione

GSK3β:

Glycogen synthase kinase 3

HAT:

Histone acetyltransferases

HD:

Huntington’s disease

HLA-DRB1:

Human leucocyte antigen DRB1

HMGB1:

High mobility group box 1

HO-1:

Haem oxygenase-1

HSP70:

Heat shock protein 70

HTT:

Huntingtin

IgE:

Immunoglobulin E

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

IQ:

Intelligence quotient

IS:

Ischemic stroke

JAK:

Janus tyrosine kinase

KA-induced:

Kainic acid

KCNT1:

Potassium sodium-activated channel subfamily T member 1

Keap1:

Kelch-like ECH-associated protein 1)

lncRNA:

Long non-coding RNAs

LPS:

Lipopolysaccharides

LRRK2 kinase:

Leucine-rich repeat kinase 2

MBP:

Myelin basic protein

MCAO:

Middle cerebral artery occlusion

MCI:

Mild cognitive impairment

mcl-1:

Myeloid cell leukemia-1

MDA:

Malondialdehyde

MDD:

Major depressive disorder

MHC-II:

Major histocompatibility complex II

mHTT:

Mutant Huntingtin

MMP:

Matrix metalloproteinase

MS:

Multiple sclerosis

mTORC1/2:

Mammalian target of rapamycin complex1/2

NAC:

N-Acetylcysteine

NFAT:

Nuclear factor of activated T cells

NF-Bp65:

Nuclear factor kappa Bp65

NFT:

Neurofibrillary tangles

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3:

NLR family pyrin domain containing 3

NMDA:

N-methyl-d-aspartate

NO:

Nitric oxide

NPCs:

Neuronal precursor cells

Nrf2:

Nuclear factor erythroid 2-related factor 2

OCD:

Obsessive compulsive disorder

PCAF:

P300/CBP-associated factor

PD:

Parkinson’s disease

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PGE2:

Prostaglandin E2

PI3K:

Phosphoinositide 3-kinase

PINK1:

PTEN-induced putative kinase 1

PPA:

Propionic acid

PPAR:

Peroxisome proliferator-activated receptor

PPRE:

PPARγ response element

PSD:

Postsynaptic density

PSEN:

Presenilin

PTEN:

Phosphatase and tensin homolog

QA-induced:

Quinolinic acid-induced

ROS:

Reactive oxygen species

RPS6KB1:

Ribosomal protein S6 kinase beta-1

RXR:

Retinoid X receptor

SE:

Status epilepsy

SEGA:

Subependymal giant cell astrocytoma

SHANK3:

SH3 and multiple ankyrin repeat domains 3

SLC6A4:

Solute carrier family 6 member 4

SNpc:

Substantia nigra pars compacta

SOCS3:

Suppressor of cytokine signaling 3

SOD:

Superoxide dismutase

SSa:

Saikosaponin a

STAT:

Signal transducers and activators of transcription

TBI:

Traumatic brain injury

Th17:

T helper 17

TLE:

Temporal lobe epilepsy

TLR-4:

Toll-like receptor

TNFRS1A:

Tumor necrosis factor receptor 1 A

TPO:

Thrombopoietin

TrkB:

Tropomyosin receptor kinase B

TSC:

Tuberous sclerosis complex

TVC:

Tetrahedral framework nucleic acid (TFNAs-VB12) complex

Tyk:

Tyrosine kinase

TZD:

Thiazolidinedione

UCP:

Uncoupling proteins

ULK1:

Autophagy activating kinase

VAL-4:

Very late antigen-4/Integrin α4β1

VPA:

Valproic acid

WHO:

World Health Organization

References

  1. Bousoik E, MontazeriAliabadi H (2018) “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol 8:287

    Article  PubMed  PubMed Central  Google Scholar 

  2. Khera R, Mehan S, Kumar S et al (2022) Role of JAK-STAT and PPAR-gamma signalling modulators in the prevention of autism and neurological dysfunctions. Mol Neurobiol. https://doi.org/10.1007/s12035-022-02819-1

    Article  PubMed  Google Scholar 

  3. Khera R, Mehan S, Bhalla S, Kumar S, Alshammari A, Alharbi M, Sadhu SS (2022) Guggulsterone mediated JAK/STAT and PPAR-gamma modulation prevents neurobehavioral and neurochemical abnormalities in propionic acid-induced experimental model of autism. Molecules 27(3):889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lindholm CK (2002) IL-2 receptor signaling through the Shb adapter protein in T and NK cells. Biochem Biophys Res Commun 296(4):929–936

    Article  CAS  PubMed  Google Scholar 

  6. He Y, Gao Y, Zhang Q, Zhou G, Cao F, Yao S (2020) IL-4 switches microglia/macrophage M1/M2 polarization and alleviates neurological damage by modulating the JAK1/STAT6 pathway following ICH. Neuroscience 437:161–171

    Article  CAS  PubMed  Google Scholar 

  7. Katz G, Pobezinsky LA, Jeurling S, Shinzawa M, Van Laethem F, Singer A (2014) T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1. Science signaling 7(340):ra83

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ahmad SF, Nadeem A, Ansari MA, Bakheet SA, Al-Ayadhi LY, Attia SM (2017) Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism. Prog Neuropsychopharmacol Biol Psychiatry 79:472–480

    Article  CAS  PubMed  Google Scholar 

  9. Jung JS, Kim DH, Kim HS (2010) Ginsenoside Rh1 suppresses inducible nitric oxide synthase gene expression in IFN-γ-stimulated microglia via modulation of JAK/STAT and ERK signaling pathways. Biochem Biophys Res Commun 397(2):323–328

    Article  CAS  PubMed  Google Scholar 

  10. Chen H, Lin W, Zhang Y, Lin L, Chen J, Zeng Y, Liu N (2016) IL-10 promotes neurite outgrowth and synapse formation in cultured cortical neurons after the oxygen-glucose deprivation via JAK1/STAT3 pathway. Sci Rep 6(1):1–16

  11. Porro C, Cianciulli A, Panaro MA (2020) The regulatory role of IL-10 in neurodegenerative diseases. Biomolecules 10(7):1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alzahrani MZ, Alshammari MA, Attia SM (2018) Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T+ Itpr3tf/J autistic mice. Eur J Pharmacol 829:70–78

  13. Kim SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, Lee YJ (2013) Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal 25(4):961–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nakashima K, Wiese S, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Taga T (1999) Developmental requirement of gp130 signaling in neuronal survival and astrocyte differentiation. J Neurosci 19(13):5429–5434

  15. Ollila S, Domènech-Moreno E, Laajanen K, Wong IP, Tripathi S, Pentinmikko N, Mäkelä TP (2018) Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway. J Clin Investig 128(1):402–414

  16. Kuroda H, Sugimoto T, Horii Y, Sawada T (2001) Signaling pathway of ciliary neurotrophic factor in neuroblastoma cell lines. Med Pediatr Oncol 36(1):118–121

    Article  CAS  PubMed  Google Scholar 

  17. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O (1995) Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol 13(1):369–398

    Article  CAS  PubMed  Google Scholar 

  18. Kleppe M, Spitzer MH, Li S, Hill CE, Dong L, Papalexi E, Levine RL (2017) Jak1 integrates cytokine sensing to regulate hematopoietic stem cell function and stress hematopoiesis. Cell Stem Cell 21(4):489–501

  19. Schindler C, Strehlow I (2000) Cytokines and STAT Signaling. Vol. 47

  20. Musso T, Johnston JA, Linnekin D, Varesio L, Rowe TK, O’Shea JJ, McVicar DW (1995) Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. J Exp Med 181(4):1425–1431

    Article  CAS  PubMed  Google Scholar 

  21. Smith GA, Uchida K, Weiss A, Taunton J (2016) Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat Chem Biol 12(5):373–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cortes JR, Perez-G M, Rivas MD, Zamorano J (2007) Kaempferol inhibits IL-4-induced STAT6 activation by specifically targeting JAK3. J Immunol 179(6):3881–3887

    Article  CAS  PubMed  Google Scholar 

  23. Henriques CM, Rino J, Nibbs RJ, Graham GJ, Barata JT (2010) IL-7 induces rapid clathrin-mediated internalization and JAK3-dependent degradation of IL-7Rα in T cells. Blood 115(16):3269–3277

    Article  CAS  PubMed  Google Scholar 

  24. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, … Leonard WJ (1994) Interaction of IL-2Rβ and γc chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266(5187):1042–1045

  25. Lai KS, Jin Y, Graham DK, Witthuhn BA, Ihle JN, Liu ET (1995) A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells. J Biol Chem 270(42):25028–25036

    Article  CAS  PubMed  Google Scholar 

  26. Verbsky JW, Bach EA, Fang YF, Yang L, Randolph DA, Fields LE (1996) Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. J Biol Chem 271(24):13976–13980

    Article  CAS  PubMed  Google Scholar 

  27. Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R (1990) Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene 5(3):277–282

    CAS  PubMed  Google Scholar 

  28. Wilks AF, Harpur AG, Kurban RR, Ralph SJ, Zürcher G, Ziemiecki A (1991) Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol 11(4):2057–2065

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, … Yancopoulos GD (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 β receptor components. Science 263(5143):92–95

  30. Finbloom DS, Winestock KD (1995) IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol 155(3):1079–1090

    Article  CAS  PubMed  Google Scholar 

  31. Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O’Shea J, Johnston JA (1995) Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med 181(1):399–404

    Article  CAS  PubMed  Google Scholar 

  32. Welham MJ, Learmonth L, Bone H, Schrader JW (1995) Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin. J Biol Chem 270(20):12286–12296

    Article  CAS  PubMed  Google Scholar 

  33. Watford WT, O’Shea JJ (2006) Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity 25(5):695–697

    Article  CAS  PubMed  Google Scholar 

  34. Villarino AV, Gadina M, O’Shea JJ, Kanno Y (2020) SnapShot: Jak-STAT Signaling II. Cell 181(7):1696–1696

    Article  CAS  PubMed  Google Scholar 

  35. Hu X, Fu M, Zhao X, Wang W (2021) The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 6(1):1–33

    Google Scholar 

  36. Dimberg A, Karlberg I, Nilsson K, Oberg F (2003) Ser727/Tyr701-phosphorylated Stat1 is required for the regulation of c-Myc, cyclins, and p27Kip1 associated with ATRA-induced G0/G1 arrest of U-937 cells. Blood 102(1):254–261

    Article  CAS  PubMed  Google Scholar 

  37. Schlee M, Hölzel M, Bernard S, Mailhammer R, Schuhmacher M, Reschke J, Bornkamm GW (2007) c-MYC activation impairs the NF-κB and the interferon response: implications for the pathogenesis of Burkitt’s lymphoma. Int J Cancer 120(7):1387–1395

  38. Xu X, Fu XY, Plate J, Chong AS (1998) IFN-γ induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Can Res 58(13):2832–2837

    CAS  Google Scholar 

  39. Stephanou A, Brar BK, Knight RA, Latchman DS (2000) Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ 7(3):329–330

    Article  CAS  PubMed  Google Scholar 

  40. Hertzog PJ (2005) Measuring Immunity || Signaling Molecules Affecting Immune Response 62–79. https://doi.org/10.1016/B978-012455900-4/50267-1

  41. Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421

    Article  CAS  PubMed  Google Scholar 

  42. Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochemical J 334(Pt 2):297–314

    Article  CAS  Google Scholar 

  43. Ruff-Jamison S et al (1994) Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. J Biol Chem 269:21933–21935

    Article  CAS  PubMed  Google Scholar 

  44. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98

    Article  CAS  PubMed  Google Scholar 

  45. Zhang M et al (2020) A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. Nature 586:434–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang Q, Gao Y, Zhang J, Li Y, Chen J, Huang R, Ma G, Wang L, Zhang Y, Nie K, Wang L (2020) L-asparaginase exerts neuroprotective effects in an SH-SY5Y-A53T model of Parkinson’s disease by regulating glutamine metabolism. Front Mol Neurosci 185

  47. Miyagi T, Gil MP, Wang X, Louten J, Chu WM, Biron CA (2007) High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J Exp Med 204(10):2383–2396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Thieu VT, Yu Q, Chang HC, Yeh N, Nguyen ET, Sehra S, Kaplan MH (2008) Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29(5):679–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Weinstein JS, Laidlaw BJ, Lu Y, Wang JK, Schulz VP, Li N, Craft J (2018) STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med 215(1):337–355

  50. Lin JX, Du N, Li P, Kazemian M, Gebregiorgis T, Spolski R, Leonard WJ (2017) Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat Commun 8(1):1–12

    Article  Google Scholar 

  51. Mui AL, Wakao HMOFA, O’farrell AM, Harada N, Miyajima A (1995) Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J 14(6):1166–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wakao H, Harada N, Kitamura T, Mui AL, Miyajima A (1995) Interleukin 2 and erythropoietin activate STAT5/MGF via distinct pathways. EMBO J 14(11):2527–2535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282(28):20059–20063

    Article  CAS  PubMed  Google Scholar 

  54. Paukku K, Valgeisdottir S, Saharinen P, Bergman M, Heldin CH, Silvennoinen O (2000) Pletelet-derived growth factor (PDGF)-induced activation of Stat5 is mediated by PDGF-b receptor and is not dependent on c-Src, Fyn, Jak1 or Jak2 kinases. Biochemical Journal 345:759–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Duetsch G, Illig T, Loesgen S, Rohde K, Klopp N, Herbon N, Wjst M (2002) STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Hum Mol Genet 11(6):613–621

  56. Shimoda K, van Deursent J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Ihle JN (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted State6 gene. Nature 380(6575):630–633

  57. Zhu J, Paul WE (2008) CD4 T cells: fates, functions, and faults. Blood 112(5):1557–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sasaki K, Zhao X, Pardee AD, Ueda R, Fujita M, Sehra S, Storkus WJ (2008) Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo. J Immunol 181(1):104–108

  59. Zhao JB, Zhang Y, Li GZ, Su XF, Hang CH (2011) Activation of JAK2/STAT pathway in cerebral cortex after experimental traumatic brain injury of rats. Neurosci Lett 498(2):147–152

    Article  CAS  PubMed  Google Scholar 

  60. Han CL, Ge M, Liu YP, Zhao XM, Wang KL, Chen N, Meng FG (2018) LncRNA H19 contributes to hippocampal glial cell activation via JAK/STAT signaling in a rat model of temporal lobe epilepsy. J Neuroinflammation 15(1):1–9

  61. Ladyman SR, Fieldwick DM, Grattan DR (2012) Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse. Reproduction 144(1):83–90

    Article  CAS  PubMed  Google Scholar 

  62. Kandalam U, Palanisamy M, Clark MA (2012) Angiotensin II induces cell growth and IL-6 mRNA expression through the JAK2-STAT3 pathway in rat cerebellar astrocytes. Jak-Stat 1(2):83–89

    Article  PubMed  PubMed Central  Google Scholar 

  63. De-Fraja C, Conti L, Magrassi L, Govoni S, Cattaneo E (1998) Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 54(3):320–330

    Article  CAS  PubMed  Google Scholar 

  64. Sabatini DM (2017) Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci USA 114(45):11818–11825. https://doi.org/10.1073/pnas.1716173114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sharma A, Mehan S (2021) Targeting PI3K-AKT/mTOR signaling in the prevention of Autism. Neurochem Int 105067

  66. Andrews MG, Subramanian L, Kriegstein AR (2020) mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex. Elife 9:e58737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ryskalin L, Lazzeri G, Flaibani M, Biagioni F, Gambardella S, Frati A, Fornai F (2017) mTOR-dependent cell proliferation in the brain. BioMed Res Int

  68. Lloyd BA, Hake HS, Ishiwata T, Farmer CE, Loetz EC, Fleshner M, Greenwood BN (2017) Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Behav Brain Res 323:56–67

  69. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302

  70. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35

    Article  CAS  PubMed  Google Scholar 

  71. LiCausi F, Hartman NW (2018) Role of mTOR complexes in neurogenesis. Int J Mol Sci 19(5):1544

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kassai H, Sugaya Y, Noda S, Nakao K, Maeda T, Kano M, Aiba A (2014) Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases. Cell Rep 7(5):1626–1639

    Article  CAS  PubMed  Google Scholar 

  73. Takei N, Nawa H (2014) mTOR signaling and its roles in normal and abnormal brain development. Front Mol Neurosci 7:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bockaert J, Marin P (2015) mTOR in brain physiology and pathologies. Physiol Rev 95(4):1157–1187

    Article  CAS  PubMed  Google Scholar 

  75. Park HK, Na DL, Lee JH, Kim JW, Ki CS (2008) Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer’s disease. J Korean Med Sci 23(2):213–217

    Article  PubMed  PubMed Central  Google Scholar 

  76. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, He Z (2008) Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322(5903):963–966

  77. Li W, Liu H, Yu M, Zhang X, Zhang Y, Liu H, Wilson JX, Huang G (2016) Folic acid alters methylation profile of JAK-STAT and long-term depression signaling pathways in Alzheimer’s disease models. Mol Neurobiol 53(9):6548–6556. https://doi.org/10.1007/s12035-015-9556-9

    Article  CAS  PubMed  Google Scholar 

  78. Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC (2014) Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radical Biol Med 74:129–144

    Article  CAS  Google Scholar 

  79. Seitz C, Hugle M, Cristofanon S, Tchoghandjian A, Fulda S (2013) The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer 132(11):2682–2693

    Article  CAS  PubMed  Google Scholar 

  80. Kim DI, Lee KH, Gabr AA, Choi GE, Kim JS, Ko SH, Han HJ (2016) Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochimica et Biophysica Acta (BBA)-Mol Cell Res 1863(11):2820–2834

  81. Liu Q, Qiu J, Liang M, Golinski J, Van Leyen K, Jung JE, Whalen MJ (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5(2):e1084–e1084

  82. Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, McFarland BC, Harrington LE, Raman C, Sabbaj S, Benveniste EN, Qin H (2014) Therapeutic efficacy of suppressing the JAK/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 192(1):59–72. https://doi.org/10.4049/jimmunol.1301513

    Article  CAS  PubMed  Google Scholar 

  83. Omeragic A, Hoque MT, Choi UY, Bendayan R (2017) Peroxisome proliferator-activated receptor-gamma: potential molecular therapeutic target for HIV-1-associated brain inflammation. J Neuroinflammation 14(1):183. https://doi.org/10.1186/s12974-017-0957-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. He TC, Chan TA, Vogelstein B, Kinzler KW (1999) PPARδ is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 99(3):335–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53(1):409–435

    Article  CAS  PubMed  Google Scholar 

  86. Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, Harris RA (2016) Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep 6(1):1–15

  87. Schintu N, Frau L, Ibba M, Caboni P, Garau A, Carboni E, Carta AR (2009) PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 29(5):954–963. https://doi.org/10.1111/j.1460-9568.2009.06657.x

    Article  PubMed  Google Scholar 

  88. Storer PD, Xu J, Chavis J, Drew PD (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis. J Neuroimmunol 161(1–2):113–122. https://doi.org/10.1016/j.jneuroim.2004.12.015

    Article  CAS  PubMed  Google Scholar 

  89. Moreno S, Farioli-Vecchioli S, Ceru MP (2004) Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 123(1):131–145

    Article  CAS  PubMed  Google Scholar 

  90. Corona JC, Duchen MR (2016) PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radical Biol Med 100:153–163

    Article  CAS  Google Scholar 

  91. Villapol S (2018) Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol Neurobiol 38(1):121–132

    Article  CAS  PubMed  Google Scholar 

  92. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. https://doi.org/10.1126/science.1072994

    Article  CAS  PubMed  Google Scholar 

  93. Liesz A (2019) The vascular side of Alzheimer’s disease. Science 365(6450):223–224

    Article  CAS  PubMed  Google Scholar 

  94. Guyant-Marechal L, Rovelet-Lecrux A, Goumidi L, Cousin E, Hannequin D, Raux G, Campion D (2007) Variations in the APP gene promoter region and risk of Alzheimer disease. Neurology 68(9):684–687

  95. Hardy J (2017) The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis.” FEBS J 284(7):1040–1044

    Article  CAS  PubMed  Google Scholar 

  96. Ishikawa A, Piao YS, Miyashita A, Kuwano R, Onodera O, Ohtake H, Takahashi H (2005) A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer’s disease. Ann Neurol 57(3):429–434

  97. Delabio R, Rasmussen L, Mizumoto I, Viani GA, Chen E, Villares J, Payao SL (2014) PSEN1 and PSEN2 gene expression in Alzheimer’s disease brain: a new approach. J Alzheimers Dis 42(3):757–760

  98. Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Hyman BT (2018) Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99(5):925–940

  99. Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P (2012) Alzheimer culprits: cellular crossroads and interplay. Cell Signal 24(9):1831–1840

    Article  CAS  PubMed  Google Scholar 

  100. Marcus JN, Schachter J (2011) Targeting post-translational modifications on tau as a therapeutic strategy for Alzheimer’s disease. J Neurogenet 25(4):127–133

    Article  CAS  PubMed  Google Scholar 

  101. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24(1):1121–1159. https://doi.org/10.1146/annurev.neuro.24.1.1121

    Article  CAS  PubMed  Google Scholar 

  102. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer‘s disease. Annu Rev Neurosci. 34:185–204. https://doi.org/10.1146/annurev-neuro-061010-113613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kumar S, Walter J (2011) Phosphorylation of amyloid beta (Aβ) peptides—a trigger for formation of toxic aggregates in Alzheimer’s disease. Aging (Albany NY) 3(8):803

    Article  PubMed  Google Scholar 

  104. De Strooper B, Woodgett J (2003) Alzheimer‘s disease: mental plaque removal. Nature 423(6938):392. https://doi.org/10.1038/423392a

    Article  CAS  PubMed  Google Scholar 

  105. Chintapaludi SR, Uyar A, Jackson HM, Acklin CJ, Wang X, Sasner M, Carter GW, Howell GR (2020) Staging Alzheimer’s disease in the brain and retina of B6. APP/PS1 mice by transcriptional profiling. J Alzheimer's Dis 73(4):1421–1434

  106. Yang L, Liu Y, Wang Y, Li J, Liu N (2021) Azeliragon ameliorates alzheimer’s disease via the janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics 76(12):1–8. https://doi.org/10.6061/CLINICS/2021/E2348

    Article  Google Scholar 

  107. Yang Y, Gao H, Liu W, Liu X, Jiang X, Li X, Wu Q, Xu Z, Zhao Q (2021) Arctium lappa L roots ameliorates cerebral ischemia through inhibiting neuronal apoptosis and suppressing AMPK/mTOR-mediated autophagy. Phytomedicine 85(January):153526. https://doi.org/10.1016/j.phymed.2021.153526

    Article  CAS  PubMed  Google Scholar 

  108. Guo C, Yang L, Luo J, Zhang C, Xia Y, Ma T, Kong L (2016) Sophoraflavanone G from Sophora alopecuroides inhibits lipopolysaccharide-induced inflammation in RAW264.7 cells by targeting PI3K/Akt, JAK/STAT and Nrf2/HO-1 pathways. Int Immunopharmacol 38:349–356. https://doi.org/10.1016/j.intimp.2016.06.021

    Article  CAS  PubMed  Google Scholar 

  109. El Sayed NS, Ghoneum MH (2020) Antia, a natural antioxidant product, attenuates cognitive dysfunction in streptozotocin-induced mouse model of sporadic Alzheimer’s disease by targeting the amyloidogenic, inflammatory, autophagy, and oxidative stress pathways. Oxid Med Cell Longev. https://doi.org/10.1155/2020/4386562

  110. Van Skike CE, Jahrling JB, Olson AB, Sayre NL, Hussong SA, Ungvari Z, Lechleiter JD, Galvan V (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment. Am J Physiology-Heart Circulatory Physiol

  111. Zhang Z, Wang X, Zhang D, Liu Y, Li L (2019) Geniposide-mediated protection against amyloid deposition and behavioral impairment correlates with downregulation of mTOR signaling and enhanced autophagy in a mouse model of Alzheimer’s disease. Aging 11(2):536–548. https://doi.org/10.18632/aging.101759

  112. Siman R, Cocca R, Dong Y (2015) The mTOR inhibitor rapamycin mitigates perforant pathway neurodegeneration and synapse loss in a mouse model of early-stage Alzheimer-type tauopathy. PLoS ONE 10(11):1–21

    Article  Google Scholar 

  113. Guo D, Xie J, Zhao J, Huang T, Guo X, Song J (2018) Resveratrol protects early brain injury after subarachnoid hemorrhage by activating autophagy and inhibiting apoptosis mediated by the Akt/mTOR pathway. NeuroReport 29(5):368–379. https://doi.org/10.1097/WNR.000000000000097510.1016/j.neuropharm.2017.11.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Guo X, Lv J, Lu J, Fan L, Huang X, Hu L, Wang J, Shen X (2018) Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy. Neuropharmacology 130:77–91

    Article  CAS  PubMed  Google Scholar 

  115. Wang C, Zhang X, Teng Z, Zhang T, Li Y (2014) Downregulation of PI3K/Akt/mTOR signaling pathway in curcumin-induced autophagy in APP/PS1 double transgenic mice. Eur J Pharmacol 740:312–320

    Article  CAS  PubMed  Google Scholar 

  116. Jahrling JB, Hernandez CM, Denner L, Dineley KT (2014) PPARγ recruitment to active ERK during memory consolidation is required for alzheimer’s disease-related cognitive enhancement. J Neurosci 34(11):4054–4063

    Article  PubMed  PubMed Central  Google Scholar 

  117. Seok H, Lee M, Shin E, Yun MR, Lee, Ho Y, Moon JH, Kim E, Lee PH, Lee BW et al (2019) Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus. Scientific Reports 9(1):1–10. https://doi.org/10.1038/s41598-019-40736-x

    Article  CAS  Google Scholar 

  118. Wang J, Ma MW, Dhandapani KM, Brann DW (2017) Regulatory role of NADPH oxidase 2 in the polarization dynamics and neurotoxicity of microglia/macrophages after traumatic brain injury. Free Radical Biol Med 113:119–131

    Article  Google Scholar 

  119. Wang Xu, Wang Y, Hu JP, Yu S, Li BK, Cui Y, Ren L, Zhang LD (2017) Astragaloside IV, a natural PPARγ agonist, reduces Aβ production in Alzheimer’s disease through inhibition of BACE1. Mol Neurobiol 54(4):2939–2949. https://doi.org/10.1007/s12035-016-9874-6

    Article  CAS  PubMed  Google Scholar 

  120. El-Din SS, Abd Elwahab S, Rashed L, Fayez S, Aboulhoda BE, Heikal OA, Galal AF, Nour ZA (2021) Possible role of rice bran extract in microglial modulation through PPAR-gamma receptors in alzheimer’s disease mice model. Metab Brain Dis 36(7):1903–1915. https://doi.org/10.1007/s11011-021-00741-4

    Article  CAS  PubMed  Google Scholar 

  121. Hosseini A, Gharibi T, Mohammadzadeh A, Ebrahimi-Kalan A, Jadidi-niaragh F, Babaloo Z, Shanehbandi D, Baghbani E, Baradaran B (2021) Ruxolitinib attenuates experimental autoimmune encephalomyelitis (EAE) development as animal models of multiple sclerosis (MS). Life Sci 276(December 2020):119395. https://doi.org/10.1016/j.lfs.2021.119395

    Article  CAS  PubMed  Google Scholar 

  122. Yin L, Chen Y, Qu Z, Zhang L, Wang Q, Zhang Q, Li L (2014) Involvement of JAK/STAT signaling in the effect of cornel iridoid glycoside on experimental autoimmune encephalomyelitis amelioration in rats. J Neuroimmunol 274(1–2):28–37. https://doi.org/10.1016/j.jneuroim.2014.06.022

    Article  CAS  PubMed  Google Scholar 

  123. Zhang J, Zeng YQ, Zhang J, Pan XD, Kang DY, Huang TW, Chen XC (2015) Tripchlorolide ameliorates experimental autoimmune encephalomyelitis by down-regulating ERK1/2-NF-κB and JAK/STAT signaling pathways. J Neurochem 133(1):104–112. https://doi.org/10.1111/jnc.13058

    Article  CAS  PubMed  Google Scholar 

  124. Yamate-Morgan H, Lauderdale K, Horeczko J, Merchant U, Tiwari-Woodruff SK (2019) Functional effects of Cuprizone-induced demyelination in the presence of the mTOR-inhibitor rapamycin. Neuroscience 406:667–683. https://doi.org/10.1016/j.neuroscience.2019.01.038

    Article  CAS  PubMed  Google Scholar 

  125. Hou H, Cao R, Miao J, Sun Y, Liu X, Song X, Guo L (2016) Fingolimod ameliorates the development of experimental autoimmune encephalomyelitis by inhibiting Akt-mTOR axis in mice. Int Immunopharmacol 30:171–178. https://doi.org/10.1016/j.intimp.2015.11.024

    Article  CAS  PubMed  Google Scholar 

  126. Niino M, Iwabuchi K, Kikuchi S, Ato M, Morohashi T, Ogata A, Tashiro K, Onoé K (2001) Amelioration of experimental autoimmune encephalomyelitis in C57BLr6 mice by an agonist of peroxisome. J Neuroimmunol 40–48

  127. Qin H, Buckley JA, Li X, Liu Y, Fox TH, Meares GP, Yu H, Yan Z, Harms AS, Li Y, Standaert DG, Benveniste EN (2016) Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J Neurosci 36(18):5144–5159. https://doi.org/10.1523/JNEUROSCI.4658-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhou W, Chen L, Hu X, Cao S, Yang J (2019) Effects and mechanism of epigallocatechin-3-gallate on apoptosis and mTOR/AKT/GSK-3β pathway in substantia nigra neurons in Parkinson rats. NeuroReport 30(2):60–65. https://doi.org/10.1097/WNR.0000000000001149

    Article  CAS  PubMed  Google Scholar 

  129. Cui W, Yang X, Chen X, Xiao D, Zhu J, Zhang M, Qin X, Ma X, Lin Y (2021) Treating LRRK2-related Parkinson’s disease by inhibiting the mTOR signaling pathway to restore autophagy. Adv Func Mater 31(38):1–13. https://doi.org/10.1002/adfm.202105152

    Article  CAS  Google Scholar 

  130. Jiang D, Peng Y (2021) The protective effect of decoction of Rehmanniae via PI3K/Akt/mTOR pathway in MPP+-induced Parkinson’s disease model cells. J Recept Signal Transduction 41(1):74–84. https://doi.org/10.1080/10799893.2020.1787445

    Article  CAS  Google Scholar 

  131. Lee Y, Cho JH, Lee S, Lee W, Chang SC, Chung HY, Moon HR, Lee J (2019) Neuroprotective effects of MHY908, a PPAR α/γ dual agonist, in a MPTP-induced Parkinson’s disease model. Brain Research 1704(June 2018):47–58. https://doi.org/10.1016/j.brainres.2018.09.036

    Article  CAS  PubMed  Google Scholar 

  132. El-Abhar H, Abd El Fattah MA, Wadie W, El-Tanbouly DM (2018) Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/SOCS-3 crosstalk in a rat model of Huntington’s disease. PLoS ONE 13(9):e0203837

    Article  PubMed  PubMed Central  Google Scholar 

  133. Singer E, Walter C, Fabbro D, Rageot D, Beaufils F, Wymann MP, Nguyen HP (2020) Brain-penetrant PQR620 mTOR and PQR530 PI3K/mTOR inhibitor reduce huntingtin levels in cell models of HD. Neuropharmacology 162:107812

  134. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6):585–595

  135. Abd-Elrahman KS, Ferguson SSG (2019) Modulation of mTOR and CREB pathways following mGluR5 blockade contribute to improved Huntington’s pathology in zQ175 mice. Mol Brain 12(1):1–9. https://doi.org/10.1186/s13041-019-0456-1

    Article  CAS  Google Scholar 

  136. Cui J, Wang G, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL (2018) Neuroprotective effect of naringin, a flavone glycoside in quinolinic acid-induced neurotoxicity: possible role of PPAR-γ Bax/Bcl-2, and caspase-3. Food Chem Toxicol 121:95–108. https://doi.org/10.1016/j.fct.2018.08.028

    Article  CAS  PubMed  Google Scholar 

  137. Chiang MC, Chern Y, Huang RN (2012) PPARgamma rescue of the mitochondrial dysfunction in Huntington’s disease. Neurobiol Dis 45(1):322–328. https://doi.org/10.1016/j.nbd.2011.08.016

    Article  CAS  PubMed  Google Scholar 

  138. Nguyen LH, Brewster AL, Clark ME, Regnier-Golanov A, Sunnen CN, Patil VV, D’Arcangelo G, Anderson AE (2015) MTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. Epilepsia 56(4):636–646. https://doi.org/10.1111/epi.12946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jeong KH, Lee DS, Kim SR (2015) Effects of eugenol on granule cell dispersion in a mouse model of temporal lobe epilepsy. Epilepsy Res 115:73–76. https://doi.org/10.1016/j.eplepsyres.2015.06.001

    Article  CAS  PubMed  Google Scholar 

  140. Ye M, Bi YF, Ding L, Zhu WW, Gao W (2016) Saikosaponin a functions as anti-epileptic effect in pentylenetetrazol induced rats through inhibiting mTOR signaling pathway. Biomed Pharmacother 81:281–287

    Article  CAS  PubMed  Google Scholar 

  141. Du M, Sun Z, Lu Y, Li YZ, Xu HR, Zeng CQ (2019) Osthole inhibits proliferation and induces apoptosis in BV-2 microglia cells in kainic acid-induced epilepsy via modulating PI3K/AKt/mTOR signalling way. Pharm Biol 57(1):238–244. https://doi.org/10.1080/13880209.2019.1588905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Jin M, Zhang B, Sun Y, Zhang S, Li X, Sik A, Bai Y, Zheng X, Liu K (2020) Involvement of peroxisome proliferator-activated receptor γ in anticonvulsant activity of α-asaronol against pentylenetetrazole-induced seizures in zebrafish

  143. Sarahian N, Mohammadi MT, Darabi S, Faghihi N (2021) Fenofibrate protects the neurovascular unit and ameliorates plasma corticosterone levels in pentylenetetrazole-induced kindling seizure in mice. Brain Res 1758(January):147343. https://doi.org/10.1016/j.brainres.2021.147343

    Article  CAS  PubMed  Google Scholar 

  144. Chuang YC, Lin TK, Huang HY, Chang WN, Liou CW, Chen SD, Chang AYW, Chan SHH (2012) Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus. J Neuroinflammation 9:1–18. https://doi.org/10.1186/1742-2094-9-184

    Article  CAS  Google Scholar 

  145. Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alsanea S, Al-Hosaini KA, Mahmood HM, Alzahrani MZ, Attia SM (2020) Inhibition of tyrosine kinase signaling by tyrphostin AG126 downregulates the IL-21/IL-21R and JAK/STAT pathway in the BTBR mouse model of autism. In NeuroToxicology (Vol. 77, Issue December). Elsevier B.V. https://doi.org/10.1016/j.neuro.2019.12.003

  146. Steinmetz AB, Stern SA, Kohtz AS, Descalzi G, Alberini CM (2018) Insulin-like growth factor II targets the mTOR pathway to reverse autism-like phenotypes in mice. J Neurosci 38(4):1015–1029. https://doi.org/10.1523/JNEUROSCI.2010-17.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Xie J, Han Q, Wei Z, Wang Y, Wang S, Chen M (2021) Phenanthrene induces autism-like behavior by promoting oxidative stress and mTOR pathway activation. Toxicology 461(July):152910. https://doi.org/10.1016/j.tox.2021.152910

    Article  CAS  PubMed  Google Scholar 

  148. Mirza R, Sharma B (2019) A selective peroxisome proliferator-activated receptor-γ agonist benefited propionic acid induced autism-like behavioral phenotypes in rats by attenuation of neuroinflammation and oxidative stress. Chem Biol Interact 311(May):108758. https://doi.org/10.1016/j.cbi.2019.108758

    Article  CAS  PubMed  Google Scholar 

  149. Mirza R, Sharma B (2019) Benefits of Fenofibrate in prenatal valproic acid-induced autism spectrum disorder related phenotype in rats. Brain Res Bull 147:36–46. https://doi.org/10.1016/j.brainresbull.2019.02.003

    Article  CAS  PubMed  Google Scholar 

  150. Bhandari R, Kuhad A (2017) Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int 103:8–23. https://doi.org/10.1016/j.neuint.2016.12.012

    Article  CAS  PubMed  Google Scholar 

  151. Yu L, Chen C, Wang LF, Kuang X, Liu K, Zhang H, Du J (2013) Neuroprotective effect of Kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-κB and STAT3 in transient focal stroke. PLoS ONE 8(2). https://doi.org/10.1371/journal.pone.0055839

  152. Xu B, He X, Sui Y, Wang X, Wang X, Ren L, Zhai YX (2019) Ginkgetin aglycone attenuates neuroinflammation and neuronal injury in the rats with ischemic stroke by modulating STAT3/JAK2/SIRT1. Folia Neuropathol 57(1):16–23. https://doi.org/10.5114/fn.2019.83827

    Article  PubMed  Google Scholar 

  153. Yang X, Hei C, Liu P, Song Y, Thomas T, Tshimanga S, Wang F, Niu J, Sun T, Andy Li P (2015) Inhibition of mTOR pathway by rapamycin reduces brain damage in rats subjected to transient forebrain Ischemia. Int J Biol Sci 11(12):1424–1435. https://doi.org/10.7150/ijbs.12930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Li H, Yang J, Wang Y, Liu Q, Cheng J, Wang F (2019) Neuroprotective effects of increasing levels of HSP70 against neuroinflammation in Parkinson’s disease model by inhibition of NF-κB and STAT3. Life Sci 234:116747

    Article  CAS  PubMed  Google Scholar 

  155. Li Q, Tian Z, Wang M, Kou J, Wang C, Rong X, Li J, Xie X, Pang X (2019) Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARγ/Nrf2/NF-κB signaling pathway. International

  156. Zhao Y, Li Z, Lu E, Sheng Q, Zhao Y (2021) Berberine exerts neuroprotective activities against cerebral ischemia/reperfusion injury through up-regulating PPAR-γ to suppress NF-κB-mediated pyroptosis. Brain Res Bull 177:22–30. https://doi.org/10.1016/j.brainresbull.2021.09.005

    Article  CAS  PubMed  Google Scholar 

  157. Al-Samhari MM, Al-Rasheed NM, Al-Rejaie S, Al-Rasheed NM, Hasan IH, Mahmoud AM, Dzimiri N (2016) Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects. Exp Biol Med 241(5):509–518. https://doi.org/10.1177/1535370215619707

    Article  CAS  Google Scholar 

  158. Wang XQ, Tang YH, Zeng GR, Wu LF, Zhou YJ, Cheng ZN, Jiang DJ (2021) Carnosic acid alleviates depression-like behaviors on chronic mild stressed mice via PPAR-γ-dependent regulation of ADPN/FGF9 pathway. Psychopharmacology 238(2):501–516

    Article  CAS  PubMed  Google Scholar 

  159. Wang Y, Song Q, Huang W, Lin Y, Wang X, Wang C, Stark GR (2021) A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses. Cell Res 31(2):206–218

  160. Ding K, Wang H, Wu Y, Zhang L, Xu J, Li T, Ding Y, Zhu L, He J (2015) Rapamycin protects against apoptotic neuronal death and improves neurologic function after traumatic brain injury in mice via modulation of the mTOR-p53-Bax axis. J Surg Res 194(1):239–247. https://doi.org/10.1016/j.jss.2014.09.026

    Article  CAS  PubMed  Google Scholar 

  161. Campolo M, Casili G, Lanza M, Filippone A, Cordaro M, Ardizzone A, Scuderi SA, Cuzzocrea S, Esposito E, Paterniti I (2021) The inhibition of mammalian target of rapamycin (mTOR) in improving inflammatory response after traumatic brain injury. J Cell Mol Med 25(16):7855–7866. https://doi.org/10.1111/jcmm.16702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Garling RJ, Watts LT, Sprague S, Digicaylioglu M (2018) Progesterone modulates mTOR in the hippocampus of mice after traumatic brain injury. Neural Regen Res 13(3):434–439. https://doi.org/10.4103/1673-5374.228725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Jiang Q, Chen J, Long X, Yao X, Zou X, Yang Y, Zhang H (2020) Phillyrin protects mice from traumatic brain injury by inhibiting the inflammation of microglia via PPARγ signaling pathway. Int Immunopharmacol 79:106083

  164. He J, Liu H, Zhong J, Guo Z, Wu J, Zhang H, Huang Z, Jiang L, Li H, Zhang Z, Liu L, Wu Y, Qi L, Sun X, Cheng C (2018) Bexarotene protects against neurotoxicity partially through a PPARγ dependent mechanism in mice following traumatic brain injury. Neurobiol Dis 117:114–124. https://doi.org/10.1016/j.nbd.2018.06.003

    Article  CAS  PubMed  Google Scholar 

  165. Deng Y, Jiang X, Deng X, Chen H, Xu J, Zhang Z, Liu G, Yong Z, Yuan C, Sun X, Wang C (2020) Pioglitazone ameliorates neuronal damage after traumatic brain injury via the PPARγ/NF-κB/IL-6 signaling pathway. Genes and Diseases 7(2):253–265. https://doi.org/10.1016/j.gendis.2019.05.002

    Article  CAS  PubMed  Google Scholar 

  166. Alers S, Löffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32(1):2–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Caccamo A, Magrì A, Medina DX, Wisely EV, López-Aranda MF, Silva AJ, Oddo S (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 12(3):370–380

    Article  CAS  PubMed  Google Scholar 

  168. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: effects on cognitive impairments. J Biol Chem 285(17):13107–13120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sun YX, Ji X, Mao X, Xie L, Jia J, Galvan V, Jin K (2014) Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer’s disease. J Alzheimers Dis 38(2):437–444

  170. Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β-secretase. J Neurosci 23(30):9796–9804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer’s disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 20(2):558–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Chamberlain S, Gabriel H, Strittmatter W, Didsbury J (2020) An exploratory phase IIa study of the PPAR delta/gamma agonist T3D–959 assessing metabolic and cognitive function in subjects with mild to moderate Alzheimer’s disease. J Alzheimers Dis 73(3):1085–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Craft S (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13(11):950–958

  174. Weinstock-Guttman B, Bhasi K, Badgett D, Tamaño-Blanco M, Minhas M, Feichter J, Ramanathan M (2008) Genomic effects of once-weekly, intramuscular interferon-β1a treatment after the first dose and on chronic dosing: relationships to 5-year clinical outcomes in multiple sclerosis patients. J Neuroimmunol 205(1–2):113–125

  175. Akbarian F, Tabatabaiefar MA, Shaygannejad V, Shahpouri MM, Badihian N, Sajjadi R, Dabiri A, Jalilian N, Noori-Daloii MR (2020) Upregulation of MTOR, RPS6KB1, and EIF4EBP1 in the whole blood samples of Iranian patients with multiple sclerosis compared to healthy controls. Metab Brain Dis 35(8):1309–1316. https://doi.org/10.1007/s11011-020-00590-7

    Article  CAS  PubMed  Google Scholar 

  176. Klotz L, Schmidt M, Giese T, Sastre M, Knolle P, Klockgether T, Heneka T (2021) And Multiple Sclerosis Patients. https://doi.org/10.4049/jimmunol.175.8.4948

  177. Kaiser CC, Shukla DK, Stebbins GT, Skias DD, Jeffery DR, Stefoski D, Katsamakis G, Feinstein DL (2009) A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis. J Neuroimmunol 211(1–2):124–130. https://doi.org/10.1016/j.jneuroim.2009.04.011

    Article  CAS  PubMed  Google Scholar 

  178. Ferret-Sena V, Maia e Silva A, Sena A, Cavaleiro I, Vale J, Derudas B, Chinetti-Gbaguidi G, Staels B (2016) Proliferator-activated receptors expression in women with multiple sclerosis

  179. He PK, Gao YY, Lyu FJ, Chen JN, Zhang YH, Nie K, Wang LM (2021) Idebenone-activating autophagic degradation of α-synuclein via inhibition of AKT-mTOR pathway in a SH-SY5Y-A53T model of Parkinson’s disease: a network pharmacological approach. Evidence-Based Complementary Alternative Med

  180. Brauer R, Bhaskaran K, Chaturvedi N, Dexter DT, Smeeth L, Douglas I (2015) Glitazone treatment and incidence of Parkinson’s disease among people with diabetes: a retrospective cohort study. PLoS Med 12(7):e1001854

    Article  PubMed  PubMed Central  Google Scholar 

  181. Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN (2013) Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol 17(6):631–638

    Article  PubMed  Google Scholar 

  182. Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA (2014) Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 164(5):1195–1200

    Article  CAS  PubMed  Google Scholar 

  183. Ching J, Amiridis S, Stylli SS, Bjorksten AR, Kountouri N, Zheng T, Kaye AH (2015) The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells. Oncotarget 6(25):21301

  184. Eftekharian MM, Noroozi R, Omrani MD, Arsang-Jang S, Komaki A, Taheri M, Ghafouri-Fard S (2018) Expression analysis of protein inhibitor of activated STAT (PIAS) genes in autistic patients. Advances in Neuroimmune Biology 7(2):129–134

    Article  CAS  Google Scholar 

  185. Eftekharian MM, Omrani MD, Komaki A, Arsang-Jang S, Taheri M, Ghafouri-Fard S (2019) Expression analysis of suppressor of cytokine signaling (SOCS) genes in blood of autistic patients. Advances in Neuroimmune Biology 7(3–4):149–154

    CAS  Google Scholar 

  186. Yui K, Sasaki H, Imataka G, Okanishi T (2018) The role of antioxidant proteins in improvement of autism core symptoms in two patients with tuberous sclerosis treated with mTOR inhibitor everolimus. Global Med Ther 1(1):1–9. https://doi.org/10.15761/gmt.1000101

  187. Patel AB, Tsilioni I, Leeman SE, Theoharides TC (2016). Erratum: immunology and inflammation. Proc Nat Acad Sci United States Am 113(45):E7138. https://doi.org/10.1073/pnas.1616587113

  188. Ghaleiha A, Mohebbi S, Nikoo M, Farokhnia M, Mohammadi M, Akhondzadeh S (2015) A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone : Effects on aberrant behavior in children with autism. Psychiatry Res 1–7. https://doi.org/10.1016/j.psychres.2015.07.043

  189. Rasgon NL, Kenna HA, Williams KE, Powers B, Wroolie T, Schatzberg AF (2010) Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study. The Scientific World J 10:321–328

    Article  CAS  Google Scholar 

  190. Cosgrove KT, Kuplicki R, Savitz J, Burrows K, Simmons WK, Khalsa SS, Paulus MP (2021) Impact of ibuprofen and peroxisome proliferator-activated receptor gamma on emotion-related neural activation: a randomized, placebo-controlled trial. Brain Behav Immun 96:135–142

  191. Bhat R, Steinman L (2009) Innate and adaptive autoimmunity directed to the central nervous system. Neuron 64(1):123–132

    Article  CAS  PubMed  Google Scholar 

  192. Ransohoff RM (2009) Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 31(5):711–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9(6):393–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ransohoff RM (2012) Animal models of multiple sclerosis: the good, the bad and the bottom line. Nat Neurosci 15(8):1074–1077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Sriram S, Rodriguez M (1997) Indictment of the microglia as the villain in multiple sclerosis. Neurology 48(2):464–470

    Article  CAS  PubMed  Google Scholar 

  196. Trapp BD, Bö L, Mörk S, Chang A (1999) Pathogenesis of tissue injury in MS lesions. J Neuroimmunol 98(1):49–56

    Article  CAS  PubMed  Google Scholar 

  197. Sakurai M, Kanazawa I (1999) Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletine. 162(2):162–168. https://doi.org/10.1016/s0022-510x(98)00322-0

  198. Clifford DB, Trotter JL (1984) Pain in multiple sclerosis. Arch Neurol 41(12):1270–1272

    Article  CAS  PubMed  Google Scholar 

  199. Eriksson M, Ben-Menachem E, Andersen O (2002) Epileptic seizures, cranial neuralgias and paroxysmal symptoms in remitting and progressive multiple sclerosis. Mult Scler J 8(6):495–499

    Article  CAS  Google Scholar 

  200. Matthews WB (1975) Paroxysmal symptoms in multiple sclerosis. J Neurol Neurosurg Psychiatry 38(6):617–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Pakenham KI (2005) Benefit finding in multiple sclerosis and associations with positive and negative outcomes. Health Psychol 24(2):123

    Article  PubMed  Google Scholar 

  202. Shibasaki H, Kuroiwa Y (1974) Painful tonic seizure in multiple sclerosis. Arch Neurol 30(1):47–51

    Article  CAS  PubMed  Google Scholar 

  203. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK, Batocchi AP (2006) pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. J Neurosci Res 84(5):1027–1036

  204. Kim YH, Chung JI, Woo HG, Jung YS, Lee SH, Moon CH et al (2010) Differential regulation of proliferation and differentiation in neural precursor cells by the Jak pathway. Stem Cells 28:1816–1828

    Article  CAS  PubMed  Google Scholar 

  205. Domingues HS, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G (2010) Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS ONE 5(11):e15531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Segal BM (2010) Th17 cells in autoimmune demyelinating disease. In Seminars in immunopathology (Vol. 32, No. 1, pp. 71–77). Springer-Verlag

  207. Liu Y, Zhang D-t, Liu X-g (2015) mTOR signaling in T cell immunity and autoimmunity. Int Rev Immunol 34:50–66

    Article  PubMed  Google Scholar 

  208. Kumar S, Patel R, Moore S, Crawford DK, Suwanna N, Mangiardi M, Tiwari-Woodruff SK (2013) Estrogen receptor β ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol Dis 56:131–144

    Article  CAS  PubMed  Google Scholar 

  209. Braissant OL, Foufelle F, Scotto CH, Dauça MI, Wahli WA (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,-beta, and-gamma in the adult rat. Endocrinology 137(1):354–366

    Article  CAS  PubMed  Google Scholar 

  210. Bernardo A, Levi G, Minghetti L (2000) Role of the peroxisome proliferator-activated receptor-γ (PPAR-γ) and its natural ligand 15-deoxy-Δ12, 14-prostaglandin J2 in the regulation of microglial functions. Eur J Neurosci 12(7):2215–2223

    Article  CAS  PubMed  Google Scholar 

  211. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Nimer SD (1995) Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expression J Liver Res 4(4–5):281–299

  212. Marx N, Sukhova G, Murphy C, Libby P, Plutzky J (1998) Macrophages in human atheroma contain PPARγ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPARγ) expression and reduction of MMP-9 activity through PPARγ activation in mononuclear phagocytes in vitro. Am J Pathol 153(1):17–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Klotz L, Sastre M, Kreutz A, Gavrilyuk V, Klockgether T, Feinstein DL, Heneka MT (2003) Noradrenaline induces expression of peroxisome proliferator activated receptor gamma (PPARγ) in murine primary astrocytes and neurons. J Neurochem 86(4):907–916

    Article  CAS  PubMed  Google Scholar 

  214. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ (2000) The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses. J Immunol 164(3):1364–1371

    Article  CAS  PubMed  Google Scholar 

  215. Schlezinger JJ, Jensen BA, Mann KK, Ryu HY, Sherr DH (2002) Peroxisome proliferator-activated receptor γ-mediated NF-κB activation and apoptosis in pre-B cells. J Immunol 169(12):6831–6841

    Article  CAS  PubMed  Google Scholar 

  216. Jiang C, Ting AT, Seed B (1998) PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391(6662):82–86

    Article  CAS  PubMed  Google Scholar 

  217. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391(6662):79–82

    Article  CAS  PubMed  Google Scholar 

  218. Bernardo A, Minghetti L (2008) Regulation of glial cell functions by PPAR-γ natural and synthetic agonists. PPAR Res

  219. Drew PD, Xu J, Storer PD, Chavis JA, Racke MK (2006) Peroxisome proliferator-activated receptor agonist regulation of glial activation: relevance to CNS inflammatory disorders. Neurochem Int 49(2):183–189

    Article  CAS  PubMed  Google Scholar 

  220. Luna-Medina R, Cortes-Canteli M, Alonso M, Santos A, Martínez A, Perez-Castillo A (2005) Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor γ activation. J Biol Chem 280(22):21453–21462

    Article  CAS  PubMed  Google Scholar 

  221. Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ (2005) PPARγ antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167(1–2):99–107

    Article  CAS  PubMed  Google Scholar 

  222. Schmidt S, Moric E, Schmidt M, Sastre M, Feinstein DL, Heneka MT (2004) Anti-inflammatory and antiproliferative actions of PPAR-γ agonists on T lymphocytes derived from MS patients. J Leukoc Biol 75(3):478–485

    Article  CAS  PubMed  Google Scholar 

  223. Klotz L, Diehl L, Dani I, Neumann H, von Oppen N, Dolf A, Knolle P (2007) Brain endothelial PPARγ controls inflammation-induced CD4+ T cell adhesion and transmigration in vitro. J Neuroimmunol 190(1–2):34–43

  224. Ramirez SH, Heilman D, Morsey B, Potula R, Haorah J, Persidsky Y (2008) Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppresses Rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes. J Immunol 180(3):1854–1865

    Article  CAS  PubMed  Google Scholar 

  225. Mestre L, Docagne F, Correa F, Loría F, Hernangomez M, Borrell J, Guaza C (2009) A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol Cell Neurosci 40(2):258–266

    Article  CAS  PubMed  Google Scholar 

  226. Duvanel CB, Honegger P, Pershadsingh H, Feinstein D, Matthieu JM (2003) Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro. J Neurosci Res 71(2):246–255

    Article  CAS  PubMed  Google Scholar 

  227. Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, Martinez G, Bronfman M (2007) Peroxisome proliferator-activated receptor γ up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 282(51):37006–37015

  228. Deuschl G, Beghi E, Fazekas F, Varga T, Christoforidi KA, Sipido E, Feigin VL (2020) The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017. The Lancet Public Heal 5(10):e551–e567

  229. Hornykiewicz O (1987) Biochemical pathophysiology of Parkinson’s disease. Parkinson’s Dis Adv Neurol 45:19–34

    CAS  Google Scholar 

  230. Hughes AJ, Daniel SE, Lees AJ (2001) Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 57(8):1497–1499

    Article  CAS  PubMed  Google Scholar 

  231. Wu Q, Shaikh MA, Meymand ES, Zhang B, Luk KC, Trojanowski JQ, Lee VMY (2020) Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo. Acta Neuropathol 140(6):831–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol 106:17–32

    Article  PubMed  Google Scholar 

  233. Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore NA, Van Swieten JC, Heutink P (2003) DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 24(3):159–160

  234. Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31(7):763–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Kumar N, Sharma N, Khera R, Gupta R, Mehan S (2021) Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain. Metab Brain Dis 36(5):911–925. https://doi.org/10.1007/s11011-021-00691-x

    Article  CAS  PubMed  Google Scholar 

  236. Repici M, Giorgini F (2019) DJ-1 in Parkinson’s disease: clinical insights and therapeutic perspectives. J Clin Med 8(9):1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Tan EK, Skipper LM (2007) Pathogenic mutations in Parkinson disease. Hum Mutat 28(7):641–653

    Article  CAS  PubMed  Google Scholar 

  238. Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, Jane JA, Marmarou A, Foulkes MA (1993) The role of secondary brain injury in determining outcome from severe head injury. J Trauma 34:216–222

    Article  CAS  PubMed  Google Scholar 

  239. Zang L, Mu YM, Lü ZH, Xue B, Ma XL, Yang GQ, Lu JM (2011) LRP16 gene causes insulin resistance in C2–C12 cells by inhibiting the IRS-1 signaling and the transcriptional activity of peroxisome proliferator actived receptor γ. Zhonghuayixue za zhi 91(20):1408–1412

  240. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304(5674):1158–1160

  241. Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Obata F (2005) An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 57(6):918–921

  242. Appel‐Cresswell S, Vilarino‐Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu‐Tu C, Trinh J, Aasly JO (2013) Alpha‐synuclein p. H50Q, a novel pathogenic mutation for Parkinson's disease. Movement disorders 28(6):811–813

  243. Keeney PM, Xie J, Capaldi RA, Bennett JP (2006) Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci 26(19):5256–5264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Schapira AH (2006) Mitochondrial disease. The Lancet 368(9529):70–82

    Article  CAS  Google Scholar 

  245. Lindqvist D, Kaufman E, Brundin L, Hall S, Surova Y, Hansson O (2012) Non-motor symptoms in patients with Parkinson’s disease–correlations with inflammatory cytokines in serum

  246. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994) Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients. Neurosci Lett 180(2):147–150

    Article  CAS  PubMed  Google Scholar 

  247. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ (2010) Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol 10:453–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T-cell lineages. Annu Rev Immunol 25:821–852 (CrossRef Medline)

    Article  CAS  PubMed  Google Scholar 

  249. O’Shea JJ, Plenge R (2012) JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36:542–550. CrossRef Medline

  250. Park H, Kang JH, Lee S (2020) Autophagy in neurodegenerative diseases: a hunter for aggregates. Int J Mol Sci 21(9):3369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Vogiatzi T, Xilouri M, Vekrellis K, Stefanis L (2008) Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J Biol Chem 283(35):23542–23556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741

    Article  CAS  PubMed  Google Scholar 

  253. Cao L, Xiong S, Wu Z, Ding L, Zhou Y, Sun H, Bian JS (2021) Anti–Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1–dependent autophagy. Sci Adv 7(5):eabc5062

  254. Wu Y, Li X, Zhu JX, Xie W, Le W, Fan Z, Pan T (2011) Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neurosignals 19(3):163–174

  255. Deplanque D, Gelé P, Pétrault O, Six I, Furman C, Bouly M, Bordet R (2003) Peroxisome proliferator-activated receptor-α activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 23(15):6264–6271

  256. Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, Carta AR (2014) Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease. Neurobiol Dis 71:280–291. https://doi.org/10.1016/j.nbd.2014.08.011

  257. Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Beal MF (2009) Impaired PGC-1α function in muscle in Huntington’s disease. Hum Mol Genet 18(16):3048–3065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Baig SS, Strong M, Quarrell OW (2016) The global prevalence of Huntington’s disease: a systematic review and discussion. Neurodegener Dis Manag 6(331):343

    Google Scholar 

  259. Jankovic J, Roos RA (2014) Chorea associated with Huntington’s disease: to treat or not to treat? Mov Disord 29(11):1414–1418

    Article  PubMed  Google Scholar 

  260. Scontrini A, Conte A, Defazio G, Fiorio M, Fabbrini G, Suppa A, Berardelli A (2009) Somatosensory temporal discrimination in patients with primary focal dystonia. J Neurol Neurosurg Psychiatry 80(12):1315–1319

  261. Reiner A, Shelby E, Wang H, DeMarch Z, Deng Y, Guley NH, Faull RL (2013) Striatal parvalbuminergic neurons are lost in Huntington’s disease: implications for dystonia. Mov Disord 28(12):1691–1699

  262. Saft C, von Hein SM, Lücke T, Thiels C, Peball M, Djamshidian A, Seppi K (2018) Cannabinoids for treatment of dystonia in Huntington’s disease. J Huntington’s Dis 7(2):167–173

  263. Delval A, Krystkowiak P, Blatt JL, Labyt E, Dujardin K, Destée A, Defebvre L (2006) Role of hypokinesia and bradykinesia in gait disturbances in Huntington’s disease. J Neurol 253(1):73–80

  264. Sebastiano DR, Soliveri P, Panzica F, Moroni I, Gellera C, Gilioli I, Canafoglia L (2012) Cortical myoclonus in childhood and juvenile onset Huntington’s disease. Parkinsonism Relat Disord 18(6):794–797

  265. Vogel CM, Drury I, Terry LC, Young AB (1991) Myoclonus in adult Huntington’s disease. Ann Neurol 29(2):213–215

    Article  CAS  PubMed  Google Scholar 

  266. Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R (2004) Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation. J Neurol 251(8):935–942

    Article  CAS  PubMed  Google Scholar 

  267. Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC, Predict-HD Investigators of the Huntington Study Group (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiat 62(12):1341–1346

    Article  Google Scholar 

  268. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ (2015) Huntington’s disease. Nature Rev Dis Primers 1:121

    Google Scholar 

  269. Hayden MR (1981) Huntington’s Chorea. Springer Verlag, Berlin

    Book  Google Scholar 

  270. Asadi S (2017) Assessment of mutation genetics in HTT (Hi-CAG), gene for induced Huntington’s disease in Tabriz, Iran. Cell Immunol Serum Biol 3(1):93–98

  271. O’Donovan MC (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983

    Article  Google Scholar 

  272. Davies SW, Mark T, Cozens BA, Raza AS, Mahal A, Mangiarini L, Bates GP (1999) From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington'sdisease. Phil Trans Royal Soc London. Series B: Biol Sci 354(1386):971–979

  273. Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Tabrizi SJ (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med 205(8):1869–1877

  274. Wild E, Magnusson A, Lahiri N, Krus U, Orth M, Tabrizi SJ, Björkqvist M (2011) Abnormal peripheral chemokine profile in Huntington’s disease. PLoS Curr 3

  275. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC (2009) Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16(1):46–56

    Article  CAS  PubMed  Google Scholar 

  276. Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103(2):253–262

    Article  CAS  PubMed  Google Scholar 

  277. Santini E, Heiman M, Greengard P, Valjent E, Fisone G (2009) Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA–induced dyskinesia. Sci Signal 2(80):ra36

    Article  PubMed  Google Scholar 

  278. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS ONE 5(4):e9979

  279. Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133(1):93–104

    Article  PubMed  Google Scholar 

  280. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N et al (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59–69

    Article  CAS  PubMed  Google Scholar 

  281. Jin YN, Hwang WY, Jo C, Johnson GV (2012) Metabolic state determines sensitivity to cellular stress in Huntington disease: normalization by activation of PPARγ. PloS one 7(1):e30406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Johri A, Chandra A, Beal MF (2013) PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radical Biol Med 62:37–46

    Article  CAS  Google Scholar 

  283. Kalonia H, Kumar P, Kumar A (2010) Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid induced neurotoxicity: possible role of peroxisome proliferator activated receptor-ϒ (PPARϒ) in Huntington’s disease. Pharmacol Biochem Behav 96(2):115–124

    Article  CAS  PubMed  Google Scholar 

  284. Vezzani Annamaria, Aronica Eleonora, Mazarati Andrey, Pittman Quentin J (2013) Epilepsy and brain inflammation. Exp Neurol 244:11–21. https://doi.org/10.1016/j.expneurol.2011.09.033

    Article  CAS  PubMed  Google Scholar 

  285. Raoof R, Jimenez-Mateos EM, Bauer S, Tackenberg B, Rosenow F, Lang J, Mooney C (2017) Cerebrospinal fluid microRNAs are potential biomarkers of temporal lobe epilepsy and status epilepticus. Sci Rep 7(1):1–17

  286. Houser CR (1990) Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res 535(2):195–204

    Article  CAS  PubMed  Google Scholar 

  287. Schipper S, Aalbers MW, Rijkers K, Swijsen A, Rigo JM, Hoogland G, Vles JSH (2016) Tonic GABAA receptors as potential target for the treatment of temporal lobe epilepsy. Mol Neurobiol 53(8):5252–5265

    Article  CAS  PubMed  Google Scholar 

  288. Steinlein OK (2014) Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res 213:1–15

    Article  PubMed  Google Scholar 

  289. Steinlein OK, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic SF, Bertrand D (1997) An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet 6(6):943–947

  290. Steinlein OK, Stoodt J, Mulley J, Berkovic S, Scheffer IE, Brodtkorb E (2000) Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia 41(5):529–535

    Article  CAS  PubMed  Google Scholar 

  291. Villa C, Colombo G, Meneghini S, Gotti C, Moretti M, Ferini-Strambi L, Combi R (2019) CHRNA2 and nocturnal frontal lobe epilepsy: identification and characterization of a novel loss of function mutation. Front Mol Neurosci 12:17

  292. Gertler T, Bearden D, Bhattacharjee A, Carvill G (2018) KCNT1-related epilepsy

  293. McTague A, Nair U, Malhotra S, Meyer E, Trump N, Gazina EV, Kurian MA (2018) Clinical and molecular characterization of KCNT1-related severe early-onset epilepsy. Neurology 90(1):e55–e66

  294. Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S, Sáenz A, Poza JJ, Galán J, López de Munain A (2002) Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 11(9):1119–1128

  295. Baulac S (2014) Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5. Prog Brain Res 213:123–139

    Article  PubMed  Google Scholar 

  296. Dibbens LM, De Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Scheffer IE (2013) Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 45(5):546–551

  297. Danbolt NC, Holmseth S, Skår A, Lehre KP, Furness DN (2004) Glutamate uptake and transporters. In Excitotoxicity in Neurological Diseases (pp. 27–49). Springer, Boston, MA

  298. Gorter JA, van Vliet EA, Aronica E, Breit T, Rauwerda H, da Silva FHL, Wadman WJ (2006) Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci 26(43):11083–11110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Turrin NP, Rivest S (2004) Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis 16(2):321–334

    Article  CAS  PubMed  Google Scholar 

  300. Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46(11):1724–1743

    Article  CAS  PubMed  Google Scholar 

  301. Voutsinos-Porche B, Koning E, Kaplan H, Ferrandon A, Guenounou M, Nehlig A, Motte J (2004) Temporal patterns of the cerebral inflammatory response in the rat lithium–pilocarpine model of temporal lobe epilepsy. Neurobiol Dis 17(3):385–402

    Article  CAS  PubMed  Google Scholar 

  302. Kuno K, Matsushima K (1994) The IL-1 receptor signaling pathway. J Leukoc Biol 56(5):542–547

    Article  CAS  PubMed  Google Scholar 

  303. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Abraham E (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290(3):C917–C924

  304. Schäfers M, Sorkin L (2008) Effect of cytokines on neuronal excitability. Neurosci Lett 437(3):188–193

    Article  PubMed  Google Scholar 

  305. Rodgers KM, Hutchinson MR, Northcutt A, Maier SF, Watkins LR, Barth DS (2009) The cortical innate immune response increases local neuronal excitability leading to seizures. Brain 132(9):2478–2486

    Article  PubMed  PubMed Central  Google Scholar 

  306. Viviani B, Gardoni F, Marinovich M (2007) Cytokines and neuronal ion channels in health and disease. Int Rev Neurobiol 82:247–263

    Article  CAS  PubMed  Google Scholar 

  307. Wang SAM, Cheng Q, Malik S, Yang JAY (2000) Interleukin-1β inhibits γ-aminobutyric acid type A (GABAA) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther 292(2):497–504

    CAS  PubMed  Google Scholar 

  308. Wang ZX, Liu Y, Young LJ, Insel TR (2000) Hypothalamic vasopressin gene expression increases in both males and females postpartum in a biparental rodent. J Neuroendocrinol 12(2):111–120

    Article  CAS  PubMed  Google Scholar 

  309. Grabenstatter HL, Del Angel YC, Carlsen J, Wempe MF, White AM, Cogswell M, Brooks-Kayal AR (2014) The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol Dis 62:73–85

  310. Hu QP, Yan HX, Peng F, Feng W, Chen FF, Huang XY, Zhang X (2021) Genistein protects epilepsy-induced brain injury through regulating the JAK2/STAT3 and Keap1/Nrf2 signaling pathways in the developing rats. 1–29. https://www.researchsquare.com/article/rs-143614/latest.pdf

  311. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Sabatini DM (2013) A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340(6136):1100–1106

  312. Panchaud N, Péli-Gulli MP, De Virgilio C (2013) Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Science signaling 6(277):ra42

    Article  PubMed  Google Scholar 

  313. Lim KC, Crino PB (2013) Focal malformations of cortical development: new vistas for molecular pathogenesis. Neuroscience 252:262–276

    Article  CAS  PubMed  Google Scholar 

  314. LaSarge CL, Danzer SC (2014) Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation. Front Mol Neurosci 7:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  315. Hong S, Xin Y, HaiQin W, GuiLian Z, Ru Z, ShuQin Z, HuQing W, Li Y, Yun D (2012) The PPARgamma agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus. Neurol Sci 33:559–566

    Article  PubMed  Google Scholar 

  316. Hong S, Xin Y, HaiQin W, GuiLian Z, Ru Z, ShuQin Z, HuQing W, Li Y, Ning B, YongNan L (2013) The PPARgamma agonist rosiglitazone prevents neuronal loss and attenuates development of spontaneous recurrent seizures through BDNF/TrkB signaling following pilocarpine-induced status epilepticus. Neurochem Int 63:405–412

    Article  CAS  PubMed  Google Scholar 

  317. Sun H, Huang Y, Yu X, Li Y, Yang J, Li R, Deng Y, Zhao G (2008) Peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after lithium pilocarpine-induced status epilepticus in rats. Int J Dev Neurosci 26:505–515

    Article  CAS  PubMed  Google Scholar 

  318. Echtay KS (2007) Mitochondrial uncoupling proteins—what is their physiological role? Free Radical Biol Med 43(10):1351–1371

    Article  CAS  Google Scholar 

  319. Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J (2006) Uncoupling proteins: a role in protection against reactive oxygen species—or not? Biochimica et Biophysica Acta (BBA)-Bioenergetics 1757(5–6):449–458

  320. Chen SD, Lin TK, Lin JW, Yang DI, Lee SY, Shaw FZ, Chuang YC (2010) Activation of calcium/calmodulin-dependent protein kinase IV and peroxisome proliferator-activated receptor γ coactivator-1α signaling pathway protects against neuronal injury and promotes mitochondrial biogenesis in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res 88(14):3144–3154

  321. Chen SD, Wu HY, Yang DI, Lee SY, Shaw FZ, Lin TK, Chuang YC (2006) Effects of rosiglitazone on global ischemia-induced hippocampal injury and expression of mitochondrial uncoupling protein 2. Biochem Biophys Res Commun 351(1):198–203

  322. Neumeyer AM, Anixt J, Chan J, Perrin JM, Murray D, Coury DL, Parker RA (2019) Identifying associations among co-occurring medical conditions in children with autism spectrum disorders. Acad Pediatr 19(3):300–306

  323. Tzanoulinou S, Musardo S, Contestabile A, Bariselli S, Casarotto G, Magrinelli E, Bellone C (2022) Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism. Mol Psychiatry 1–15

  324. Uchino S, Waga C (2013) SHANK3 as an autism spectrum disorder-associated gene. Brain Develop 35(2):106–110

    Article  Google Scholar 

  325. Baron MK, Boeckers TM, Vaida B, Faham S, Gingery M, Sawaya MR, Salyer D, Gundelfinger ED, Bowie JU (2006) An architectural framework that may lie at the core of the postsynaptic density. Science 311:531–535

    Article  CAS  PubMed  Google Scholar 

  326. Meyer G, Varoqueaux F, Neeb A, Oschlies M, Brose N (2004) The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology 47:724–733

    Article  CAS  PubMed  Google Scholar 

  327. Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, Zuffardi O (2001) Disruption of the ProSAP2 gene in at(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet 69:261–268 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders vol. 5, Author Washington DC

  328. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH et al (2004) Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 75:862–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  329. Maussion G, Carayol J, Lepagnol-Bestel AM, Tores F, Loe-Mie Y, Milbreta U et al (2008) Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism. Hum Mol Genet 17:2541–2551

    Article  CAS  PubMed  Google Scholar 

  330. Yoo HJ, Cho IH, Park M, Cho E, Cho SC, Kim BN et al (2008) Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res 62:66–69

    Article  CAS  PubMed  Google Scholar 

  331. Kazim SF, Cardenas-Aguayo MDC, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K (2015) Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats. PLoS ONE 10(3):e0118627

    Article  PubMed  PubMed Central  Google Scholar 

  332. Kaur N, Lu B, Monroe RK, Ward SM, Halvorsen SW (2005) Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons. J Neurochem 92(6):1521–1530

    Article  CAS  PubMed  Google Scholar 

  333. Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Ghilardi N (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells. Nat Immunol 7(9):929–936

  334. Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Hunter CA (2006) Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7(9):937–945

  335. Shuai K (2006) Regulation of cytokine signaling pathways by PIAS proteins. Cell Res 16(2):196–202

    Article  CAS  PubMed  Google Scholar 

  336. Gisselbrecht S (1999) The CIS/SOCS proteins: a family of cytokine-inducible regulators of signaling. Eur Cytokine Netw 10(4):463–470

    CAS  PubMed  Google Scholar 

  337. Subramanian M, Timmerman CK, Schwartz JL, Pham DL, Meffert MK (2015) Characterizing autism spectrum disorders by key biochemical pathways. Front Neurosci 9:313

    Article  PubMed  PubMed Central  Google Scholar 

  338. Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309:83–94

    Article  CAS  PubMed  Google Scholar 

  339. Nicolini C, Ahn Y, Michalski B, Rho JM, Fahnestock M (2015) Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Acta Neuropathol Commun 3(1):1–13

    Article  Google Scholar 

  340. Tordjman S, Davlantis KS, Georgieff N, Geoffray MM, Speranza M, Anderson GM, … Dawson G (2015) Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives. Front Pediatr 3:1

  341. Winden KD, Ebrahimi-Fakhari D, Sahin M (2018) Abnormal mTOR activation in autism. Annu Rev Neurosci 41:1–23

    Article  CAS  PubMed  Google Scholar 

  342. Tilot AK, Frazier TW, Eng C (2015) Balancing proliferation and connectivity in PTEN-associated autism spectrum disorder. Neurotherapeutics 12(3):609–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  343. Lugo JN, Smith GD, Arbuckle EP, White J, Holley AJ, Floruta CM, Okonkwo O (2014) Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci 7:27

  344. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Caron MG (2008) Role of GSK3β in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci 105(4):1333–1338

  345. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Parada LF (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50(3):377–388

  346. Kilincaslan A, Kok BE, Tekturk P, Yalcinkaya C, Ozkara C et al (2017) Beneficial effects of everolimus on autism and attention-deficit/hyperactivity disorder symptoms in a group of patients with tuberous sclerosis complex. J Child AdolescPsychopharmacol 27:383–388

    Article  CAS  Google Scholar 

  347. Ehninger D, Silva AJ (2011) Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends Mol Med 17:78–87

    Article  CAS  PubMed  Google Scholar 

  348. Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O et al (2012) Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 3:1292 ([Crossref])

    Article  PubMed  Google Scholar 

  349. Morgan JT, Chana G, Abramson I, Semendeferi K, Courchesne E, Everall IP (2012) Abnormal microglial–neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res 1456:72–81

    Article  CAS  PubMed  Google Scholar 

  350. Tetreault NA, Hakeem AY, Jiang S, Williams BA, Allman E, Wold BJ, Allman JM (2012) Microglia in the cerebral cortex in autism. J Autism Dev Disord 42(12):2569–2584

    Article  PubMed  Google Scholar 

  351. Cohly HH, Panja A (2005) International Review of Neurobiology. Immunological Findings in Autism 71: 317-741. https://doi.org/10.1016/s0074-7742(05)71013-8

  352. Feng J, Chen X, Lu S, Li W, Yang D, Su W, Shen J (2018) Naringin attenuates cerebral ischemia-reperfusion injury through inhibiting peroxynitrite-mediated mitophagy activation. Mol Neurobiol 55(12):9029–9042

  353. Rordorf G, Koroshetz WJ, Copen WA, Cramer SC, Schaefer PW, Budzik RF, Gonzalez G (1998) Regional ischemia and ischemic injury in patients with acute middle cerebral artery stroke as defined by early diffusion-weighted and perfusion-weighted MRI. Stroke 29(5):939–943

  354. Luo D, Zhang Y, Yuan X, Pan Y, Yang L, Zhao Y, Zhou Y (2019) Oleoylethanolamide inhibits glial activation via moudulating PPARα and promotes motor function recovery after brain ischemia. Pharmacol Res 141:530–540

  355. DeMars KM, McCrea AO, Siwarski DM, Sanz BD, Yang C, Candelario-Jalil E (2018) Protective effects of L-902,688, a prostanoid EP4 receptor agonist, against acute blood-brain barrier damage in experimental ischemic stroke. Front Neurosci 12:89

    Article  PubMed  PubMed Central  Google Scholar 

  356. Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40(5):e331–e339

    Article  PubMed  Google Scholar 

  357. Tak HJ, Jang SH (2014) Relation between aphasia and arcuate fasciculus in chronic stroke patients. BMC Neurol 14(1):1–5

    Article  Google Scholar 

  358. Flöel A, Buyx A, Breitenstein C, Lohmann H, Knecht S (2005) Hemispheric lateralization of spatial attention in right-and left-hemispheric language dominance. Behav Brain Res 158(2):269–275

    Article  PubMed  Google Scholar 

  359. Ocklenburg S, Beste C, Arning L, Peterburs J, Güntürkün O (2014) The ontogenesis of language lateralization and its relation to handedness. Neurosci Biobehav Rev 43:191–198

    Article  PubMed  Google Scholar 

  360. Bishop DV (2013) Cerebral asymmetry and language development: cause, correlate, or consequence? Science 340(6138):1230531

    Article  PubMed  PubMed Central  Google Scholar 

  361. Bowers JM, Perez-Pouchoulen M, Edwards NS, McCarthy MM (2013) Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs order of maternal retrieval. J Neurosci 33(8):3276–3283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  362. Vargha-Khadem F, Gadian DG, Copp A, Mishkin M (2005) FOXP2 and the neuroanatomy of speech and language. Nat Rev Neurosci 6(2):131–138

    Article  CAS  PubMed  Google Scholar 

  363. Fisher SE, Vargha-Khadem F, Watkins KE, Monaco AP, Pembrey ME (1998) Localisation of a gene implicated in a severe speech and language disorder. Nat Genet 18(2 February):168–70

    Article  CAS  PubMed  Google Scholar 

  364. Wilcke A, Ligges C, Burkhardt J, Alexander M, Wolf C, Quente E, Kirsten H (2012) Imaging genetics of FOXP2 in dyslexia. Eur J Hum Genet 20(2):224–229

  365. Shu W, Cho JY, Jiang Y, Zhang M, Weisz D, Elder GA, Buxbaum JD (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci 102(27):9643–9648

  366. Yi JH, Park SW, Kapadia R, Vemuganti R (2007) Role of transcription factors in mediating post-ischemic cerebral inflammation and brain damage. Neurochem Int 50:1014–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  367. Gupta YK, Chauhan A (2011) Potential of immunosuppressive agents in cerebral ischaemia. Indian J Med Res 133(1):15

    CAS  PubMed  PubMed Central  Google Scholar 

  368. Chauhan A, Sharma U, Jagannathan NR, Reeta KH, Gupta YK (2011) Rapamycin protects against middle cerebral artery occlusion induced focal cerebral ischemia in rats. Behav Brain Res 225(2):603–609

    Article  CAS  PubMed  Google Scholar 

  369. Urbanek T, Kuczmik W, Basta-Kaim A, Gabryel B (2014) RETRACTED: Rapamycin induces of protective autophagy in vascular endothelial cells exposed to oxygen–glucose deprivation

  370. Yin L, Ye S, Chen Z, Zeng Y (2012) Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice. Int J Neurosci 122(12):748–756

    Article  CAS  PubMed  Google Scholar 

  371. Buckley KM, Hess DL, Sazonova IY, Periyasamy-Thandavan S, Barrett JR, Kirks R, … Hill WD (2014) Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp Trans stroke Med 6(1):1–9

  372. Fletcher L, Evans TM, Watts LT, Jimenez DF, Digicaylioglu M (2013) Rapamycin treatment improves neuron viability in an in vitro model of stroke. PLoS ONE 8(7):e68281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  373. Kwon YK, Choi SJ, Kim CR, Kim JK, Kim YJ, Choi JH, Shin DH (2016) Antioxidant and cognitive-enhancing activities of Arctium lappa L. roots in Aβ 1–42-induced mouse model. Appl Biol Chem 59(4), 553–565.

  374. Chen FA (2013) Antioxidant activity of Arctium lappa L. and its effect on biochemical parameters in exercised rats. Asian J Chem 25:1970–1974

    Article  Google Scholar 

  375. Kim YJ, Kang SC, NamKoong S, Choung MG, Sohn EH (2012) Anti-inflammatory effects by Arctium lappa L. root extracts through the regulation of ICAM-1 and nitric oxide. Korean J Plant Resour 25(1):1–6.

  376. Ricote M, Glass CK (2007) PPARs and molecular mechanisms of transrepression. Biochimica et Biophysica Acta (BBA)-Mol Cell BioloLipids 1771(8):926–935

  377. Sauer S (2015) Ligands for the nuclear peroxisome proliferator-activated receptor gamma. Trends Pharmacol Sci 36(10):688–704

    Article  CAS  PubMed  Google Scholar 

  378. Stringaris A (2017) Editorial: What is depression? J Child Psychol Psychiatry 58:1287–1289

    Article  PubMed  Google Scholar 

  379. Żmudzka E, Sałaciak K, Sapa J, Pytka K (2018) Serotonin receptors in depression and anxiety: Insights from animal studies. Life Sci 210:106–124

    Article  PubMed  Google Scholar 

  380. Ménard C, Hodes GE, Russo SJ (2016) Pathogenesis of depression: insights from human and rodent studies. Neuroscience 321:138–162

    Article  PubMed  Google Scholar 

  381. Ogłodek E, Szota A, Just M, Moś D, Araszkiewicz A (2014) The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol Rep 66(5):776–781

    Article  PubMed  Google Scholar 

  382. Patel A (2013) The role of inflammation in depression. PsychiatrDanub 25(Suppl 2):S216–S223

    Google Scholar 

  383. Willner P (2017) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol stress 6:78–93

    Article  PubMed  Google Scholar 

  384. Wang Q, Dong X, Li N, Wang Y, Guan X, Lin Y, Xu T (2018) JSH-23 prevents depressive-like behaviors in mice subjected to chronic mild stress: Effects on inflammation and antioxidant defense in the hippocampus. Pharmacol Biochem Behav 169:59–66

  385. Wang YL, Han QQ, Gong WQ, Pan DH, Wang LZ, Hu W, Liu Q (2018) Microglial activation mediates chronic mild stress-induced depressive-and anxiety-like behavior in adult rats. J Neuroinflammation 15(1):1–14

  386. McNally L, Bhagwagar Z, Hannestad J (2008) Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr 13(6):501–510

    Article  PubMed  Google Scholar 

  387. Jabally YA, Seri S, Cavanna AE (2016) Neuropsychiatric manifestations in inflammatory neuropathies: a systematic review. Muscle Nerve 54(1):1–8

    Article  Google Scholar 

  388. Yang K, Xie G, Zhang Z, Wang C, Li W, Zhou W, Tang Y (2007) Levels of serum interleukin (IL)-6, IL-1β, tumour necrosis factor-α and leptin and their correlation in depression. Aust N Z J Psychiatry 41(3):266–273

    Article  PubMed  Google Scholar 

  389. Majd M, Saunders EF, Engeland CG (2020) Inflammation and the dimensions of depression: a review. Front Neuroendocrinol 56:100800

    Article  PubMed  Google Scholar 

  390. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiat 67(5):446–457

    Article  CAS  PubMed  Google Scholar 

  391. Chourbaji S, Urani A, Inta I, Sanchis-Segura C, Brandwein C, Zink M, Gass P (2006) IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol Dis 23(3):587–594

  392. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374(1):1–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  393. Guan X, Wang Q, Liu M, Sun A, Li X (2021) Possible involvement of the IL-6/JAK2/STAT3 pathway in the hypothalamus in depressive-like behavior of rats exposed to chronic mild stress. Neuropsychobiology 80(4):279–287

    Article  CAS  PubMed  Google Scholar 

  394. Feinstein DL (2003) Therapeutic potential of peroxisome proliferator-activated receptor agonists for neurological disease. Diabetes Technol Ther 5(1):67–73

    Article  CAS  PubMed  Google Scholar 

  395. García-Bueno B, Pérez-Nievas BG, Leza JC (2010) Is there a role for the nuclear receptor PPARγ in neuropsychiatric diseases? Int J Neuropsychopharmacol 13(10):1411–1429

    Article  PubMed  Google Scholar 

  396. García-Bueno B, Caso JR, Pérez-Nievas BG, Lorenzo P, Leza JC (2007) Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats. Neuropsychopharmacology 32(6):1251–1260

    Article  PubMed  Google Scholar 

  397. Ahmed AAE, Al-Rasheed NM, Al-Rasheed NM (2009) Antidepressant-like effects of rosiglitazone, a PPARγ agonist, in the rat forced swim and mouse tail suspension tests. Behav Pharmacol 20(7):635–642

    Article  CAS  Google Scholar 

  398. Sadaghiani MS, Javadi-Paydar M, Gharedaghi MH, Fard YY, Dehpour AR (2011) Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. Behav Brain Res 224(2):336–343

    Article  CAS  PubMed  Google Scholar 

  399. Xiong Y, Mahmood A, Meng Y, Zhang Y, Zhang ZG, Morris DC, Chopp M (2012) Neuroprotective and neurorestorative effects of thymosin β4 treatment following experimental traumatic brain injury. Ann N Y Acad Sci 1270(1):51–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  400. Maas AI, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, Francony G (2017) Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol 16(12):987–1048

  401. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136(1):28–42

    Article  PubMed  PubMed Central  Google Scholar 

  402. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Sharp DJ (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70(3):374–383

  403. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487

  404. Jones PA, Andrews PJ, Midgley S, Anderson SI, Piper IR, Tocher JL, Housley AM, Corrie JA, Slattery J, Dearden NM (1994) Measuring the burden of secondary insults in head-injured patients during intensive care. J NeurosurgAnesthesiol 6:4–14

    CAS  Google Scholar 

  405. Yamauchi K, Osuka K, Takayasu M, Usuda N, Nakazawa A, Nakahara N, Yoshida J (2006) Activation of JAK/STAT signalling in neurons following spinal cord injury in mice. J Neurochem 96(4):1060–1070

  406. Satriotomo I, Bowen KK, Vemuganti R (2006) JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem 98(5):1353–1368

    Article  CAS  PubMed  Google Scholar 

  407. Suzuki S, Tanaka K, Nogawa S, Dembo T, Kosakai A, Fukuuchi Y (2001) Phosphorylation of signal transducer and activator of transcription-3 (Stat3) after focal cerebral ischemia in rats. Exp Neurol 170(1):63–71

    Article  CAS  PubMed  Google Scholar 

  408. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  409. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590

    Article  CAS  PubMed  Google Scholar 

  410. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  411. Lin H, Tang H, Davis FB, Davis PJ (2011) Resveratrol and apoptosis. Ann N Y Acad Sci 1215:79–88

    Article  CAS  PubMed  Google Scholar 

  412. Bastianetto S, Ménard C, Quirion R (2015) Neuroprotective action of resveratrol. Biochimica et Biophysica Acta (BBA)-Mol Basis Dis 1852(6):1195–1201

  413. Qu XY, Li QJ, Zhang HM, Zhang XJ, Shi PH, Zhang XJ, Wang SQ (2016) Protective effects of phillyrin against influenza A virus in vivo. Arch Pharmacal Res 39(7):998–1005

  414. Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L, Farrar WL (2000) Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists: PPARγ co-association with transcription factor NFAT. J Biol Chem 275(7):4541–4544

    Article  CAS  PubMed  Google Scholar 

  415. Park EJ, Park SY, Joe EH, Jou I (2003) 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. J Biol Chem 278(17):14747–14752

    Article  CAS  PubMed  Google Scholar 

  416. Li Y, Xu L, Zeng K, Xu Z, Suo D, Peng L, Yang L (2017) Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses. Brain Behav Immun 66:289–301

  417. Panzer U, Zahner G, Wienberg U, Steinmetz OM, Peters A, Turner JE, Paust HJ, Wolf G, Stahl RA, Schneider A (2008) 15-deoxy-Delta 12,14-prostaglandin J2 inhibits INF-gamma induced JAK/STAT1 signalling pathway activation and IP-10/CXCL10 expression in mesangial cells. Nephrol Dial Transplant. 23(12):3776–85. https://doi.org/10.1093/ndt/gfn361

    Article  CAS  PubMed  Google Scholar 

  418. Yu JH, Kim KH, Kim H (2007) SOCS 3 and PPAR-gamma ligands inhibit the expression of IL-6 and TGF-beta1 by regulating JAK2/STAT3 signaling in pancreas. Int J Biochem Cell Biol 40(4):677–688. https://doi.org/10.1016/j.biocel.2007.10.007

    Article  CAS  PubMed  Google Scholar 

  419. Zhang L, Fang Y, Cheng X, Lian Y, Xu H, Zeng Z, Zhu H (2017) TRPML1 participates in the progression of Alzheimer’s disease by regulating the PPARγ/AMPK/Mtorsignalling pathway. Cell Physiol Biochem 43(6):2446–2456

    Article  CAS  PubMed  Google Scholar 

  420. Zhao JL, Wei C, Xiao X, Dong YH, Tan B, Yu J, Xie R (2020) Expression of TNF-α and IL-β can be suppressed via the PPAR-γ/mTOR signaling pathway in BV-2 microglia: A potential anti-inflammation mechanism. Mol Med Rep 22(4):3559–3565

  421. San YZ, Liu Y, Zhang Y, Shi PP, Zhu YL (2015) Peroxisome proliferator-activated receptor-γ agonist inhibits the mammalian target of rapamycin signaling pathway and has a protective effect in a rat model of status epilepticus. Mol Med Rep 12(2):1877–1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  422. Limor R, Sharon O, Knoll E, Many A, Weisinger G, Stern N (2008) Lipoxygenase-derived metabolites are regulators of peroxisome proliferator-activated receptor γ-2 expression in human vascular smooth muscle cells. Am J Hypertens 21(2):219–223

    Article  CAS  PubMed  Google Scholar 

  423. Liu YC, Gao XX, Zhang ZG, Lin ZH, Zou QL (2017) PPAR gamma coactivator 1 beta (PGC-1β) reduces mammalian target of rapamycin (mTOR) expression via a SIRT1-dependent mechanism in neurons. Cell Mol Neurobiol 37(5):879–887

    Article  CAS  PubMed  Google Scholar 

  424. Chen M, Puschmann TB, Wilhelmsson U, Örndal C, Pekna M, Malmgren K, Pekny M (2017) Neural progenitor cells in cerebral cortex of epilepsy patients do not originate from astrocytes expressing GLAST. Cereb Cortex 27(12):5672–5682

  425. del Zoppo GJ (2010) The neurovascular unit in the setting of stroke. J Intern Med 267:156–171

    Article  PubMed  PubMed Central  Google Scholar 

  426. Jiao GE, Yan LIU, Qiang LI, Xia GUO, Ling GU, Gui Z, Zhu YP (2013) Resveratrol induces apoptosis and autophagy in T-cell acute lymphoblastic leukemia cells by inhibiting Akt/mTOR and activating p38-MAPK. Biomed Environ Sci 26(11):902–911

    Google Scholar 

  427. Lee HS, Han J, Lee SH, Park JA, Kim KW (2010) Meteorin promotes the formation of GFAP-positive glia via activation of the Jak-STAT3 pathway. J Cell Sci 123(11):1959–1968

    Article  CAS  PubMed  Google Scholar 

  428. Maghsoumi-Norouzabad L, Alipoor B, Abed R, Eftekhar Sadat B, Mesgari-Abbasi M, AsghariJafarabadi M (2016) Effects of Arctium lappaL. (Burdock) root tea on inflammatory status and oxidative stress in patients with knee osteoarthritis. Int J Rheum Dis 19(3):255–261

    Article  CAS  PubMed  Google Scholar 

  429. Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells. J Biol Chem 281(46):34785–34795

    Article  CAS  PubMed  Google Scholar 

  430. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Human Genet 81(6):1289–1297

  431. Park C, Li S, Cha E, Schindler C (2000) Immune response in Stat2 knockout mice. Immunity 13(6):795–804

    Article  CAS  PubMed  Google Scholar 

  432. Rajnish K. Chaturvedi M, Flint Beal (2008) PPAR: a therapeutic target in Parkinson’s disease. 106(2):506–518. https://doi.org/10.1111/j.1471-4159.2008.05388.x

  433. Velazquez L, Mogensen KE, Barbieri G, Fellous M, Uzé G, Pellegrini S (1995) Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-α/β and for signal transduction. J Biol Chem 270(7):3327–3334

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors express their gratitude to Chairman, Mr. Parveen Garg, and Director, Dr. G. D. Gupta, ISF College of Pharmacy, Moga (Punjab), India, for their excellent vision and support.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Punjab, Moga, India

    Sumit Kumar & Sidharth Mehan

  2. Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC, 27516, USA

    Acharan S. Narula

Authors
  1. Sumit Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sidharth Mehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Acharan S. Narula
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Writing—the original draft of the review, Sumit Kumar; conceptualization, Acharan S Narula; original concept, supervision, Sidharth Mehan. All authors agree to be accountable for all aspects of work, ensuring integrity and accuracy.

Corresponding author

Correspondence to Sidharth Mehan.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Authors approve for submitting the publication.

Conflict of interest

The authors declare conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, S., Mehan, S. & Narula, A.S. Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions. J Mol Med 101, 9–49 (2023). https://doi.org/10.1007/s00109-022-02272-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-022-02272-6

Keywords

Search

Navigation