Skip to main content

Advertisement

SpringerLink
Log in

Signaling Pathways Involved in the Neuroprotective Effect of Osthole: Evidence and Mechanisms

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Neurodegenerative diseases constitute a major threat to human health and are usually accompanied by progressive structural and functional loss of neurons. Abnormalities in synaptic plasticity are involved in neurodegenerative disorders. Aberrant cell signaling cascades play a predominant role in the initiation, progress as well as in the severity of these ailments. Notch signaling is a pivotal role in the maintenance of neural stem cells and also participates in neurogenesis. PI3k/Akt cascade regulates different biological processes including cell proliferation, apoptosis, and metabolism. It regulates neurotoxicity and mediates the survival of neurons. Moreover, the activated BDNF/TrkB cascade is involved in promoting the transcription of genes responsible for cell survival and neurogenesis. Despite significant progress made in delineating the underlying pathological mechanisms involved and derangements in cellular metabolic promenades implicated in these diseases, satisfactory strategies for the clinical management of these ailments are yet to be achieved. Therefore, the molecules targeting these cell signaling cascades may emerge as useful leads in developing newer management strategies. Osthole is an important ingredient of traditional Chinese medicinal plants, often found in various plants of the Apiaceae family and has been observed to target these aforementioned mediators. Until now, no review has been aimed to discuss the possible molecular signaling cascades involved in osthole-mediated neuroprotection at one platform. The current review aimed to explore the interplay of various mediators and the modulation of the different molecular signaling cascades in osthole-mediated neuroprotection. This review could open new insights into research involving diseases of neuronal origin, especially the effect on neurodegeneration, neurogenesis, and synaptic plasticity. The articles gathered to compose the current review were extracted by using the PubMed, Scopus, Science Direct, and Web of Science databases. A methodical approach was used to integrate and discuss all published original reports describing the modulation of different mediators by osthole to confer neuroprotection at one platform to provide possible molecular pathways. Based on the inclusion and exclusion criteria, 32 articles were included in the systematic review. Moreover, literature evidence was also used to construct the biosynthetic pathway of osthole. The current review reveals that osthole promotes neurogenesis and neuronal functioning via stimulation of Notch, BDNF/Trk, and P13k/Akt signaling pathways. It upregulates the expression of various proteins, such as BDNF, TrkB, CREB, Nrf-2, P13k, and Akt. Activation of Wnt by osthole, in turn, regulates downstream GSK-1β to inhibit tau phosphorylation and β-catenin degradation to prevent neuronal apoptosis. The activation of Wnt and inhibition of oxidative stress, Aβ, and GSK-3β mediated β-catenin degradation by osthole might also be involved in mediating the protection against neurodegenerative diseases. Furthermore, it also inhibits neuroinflammation by suppressing MAPK/NF-κB-mediated transcription of genes involved in the generation of inflammatory cytokines and NLRP-3 inflammasomes. This review delineates the various underlying signaling pathways involved in mediating the neuroprotective effect of osthole. Modulation of Notch, BDNF/Trk, MAPK/NF-κB, and P13k/Akt signaling pathways by osthole confers protection against neurodegenerative diseases. The preclinical effects of osthole suggest that it could be a valuable molecule in inspiring the development of new drugs for the management of neurodegenerative diseases and demands clinical studies to explore its potential. An effort has been made to unify the varied mechanisms and target sites involved in the neuroprotective effect of osthole. The comprehensive description of the molecular pathways in the present work reflects its originality and thoroughness. The reviewed literature findings may be extrapolated to suggest the role of othole as a “biological response modifier” which contributes to neuroprotection through kinase modulatory, immunomodulatory, and anti-oxidative activity, which is documented even at lower doses. The current review attempts to emphasize the gaps in the existing literature which can be explored in the future.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Abbreviations

ADAM-10:

A Disintegrin and Metalloproteinase 10

APP:

Amyloid precursor protein

APP/PS1:

Amyloid precursor protein/human presenilin-1

ARE:

Antioxidant response element

Aβ:

Amyloid beta

BACE1:

Beta-site APP-cleaving enzyme 1

Bax:

Bcl-2-associated X protein

Bcl-2:

B-cell lymphoma 2

BDNF:

Brain-derived neurotrophic factor

cAMP:

Cyclic adenosine monophosphate

CBF1:

C promoter binding factor

COX-2:

Cyclooxygenase-2

CREB:

CAMP-response element-binding protein

CSD:

Chronic sleep deprivation

CSL:

CBF1/Suppressor of Hairless/Lag-1

CYP1A2:

Cytochrome P450 family 1 subfamily A polypeptide 2

CYP2E1:

Cytochrome P450 family 2 subfamily E member 1

CYP2C9:

Cytochrome P450 family 2 subfamily C polypeptide 9

CYP2C11:

Cytochrome P450 family 1 subfamily C polypeptide 11

DAG:

Diacylglycerol

DAPT:

N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester

ERK:

Extracellular signal-regulated kinase

GCLM:

Glutamate-cysteine ligase modifier subunit

GDNF:

Glial cell line-derived neurotrophic factor

GSH:

Reduced glutathione

GSK-1β:

Glycogen synthase kinase 1-beta

Hes-1:

Hairy and enhancer of split-1

Hes-1/5:

Hairy and enhancer of split-1 and 5

HO-1:

Hemeoxygenase-1

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

IP3:

Inositol 1,4,5-trisphosphate

cJNK or JNK:

C-Jun N-terminal Kinase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinases

MCAO/R:

Middle cerebral artery occlusion and reperfusion

MDA:

Malondialdehyde

MAML:

Mastermind-like

MML1-3:

Mastermind-like 1–3

MPO:

Myeloperoxidase, MWM, Morris Water Maze

NF-κB:

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

NICD:

Notch intracellular domain

NLRP-3:

Node-like receptor protein-3

NMDA:

N-methyl-D-aspartate

NQO1:

NADPH quinone dehydrogenase 1

Nrf-2:

Nuclear factor erythroid 2–related factor 2

NSCs:

Neuronal stem cells

OFT:

Open field test

OGD:

Oxygen and glucose deprived

OGD/R:

Oxygen and glucose deprived and reperfusion

pCaMkII:

P-calcium/calmodulin-dependent protein kinase II

PI3K:

Phosphoinositide 3-kinase

PIP3:

Phosphatidylinositol-3,4,5-trisphosphate

PKC:

Protein Kinase C

PLCγ:

Phospholipase C gamma

PS1:

Presenilin 1

RBP-Jκ:

Recombining binding protein J-kappa

ROS:

Reactive oxygen species

SAH:

Subarachnoid hemorrhage

SD:

Sprague Dawley

SOD:

Superoxide dismutase

SYS:

Synaptophysin

TCF:

T-cell factor

TNF-α:

Tumor necrosis factor-alpha

TrkB:

Tropomyosin receptor kinase B

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

Wnt:

Wingless/integrated

References

  1. Süzgeç-Selçuk S, Dikpınar T (2021) Phytochemical evaluation of the Ferulago genus and the pharmacological activities of its coumarin constituents. J Herb Med 25:100415

  2. Medina FG, Marrero JG, Macías-Alonso M, González MC, Córdova-Guerrero I, García AG, Osegueda-Robles S (2015) Coumarin heterocyclic derivatives: Chemical synthesis and biological activity. Nat Prod Rep 32(10):1472–507

  3. Stringlis IA, De Jonge R, Pieterse CM (2019) The age of coumarins in plant–microbe interactions. Plant Cell Physiol 60(7):1405–1419

  4. You L, Feng S, An R, Wang X (2009) Osthole: a promising lead compound for drug discovery from a traditional Chinese medicine (TCM). Nat Prod Commun 4(2):1934578X0900400227

    Google Scholar 

  5. You L, Feng S, An R, Wang X (2009) Osthole: a promising lead compound for drug discovery from a traditional Chinese medicine (TCM). Nat Prod Commun 4(2):297–302

    CAS  PubMed  Google Scholar 

  6. Zheng H, Chen Y, Guo Q, Wei H, Yue J, Zhou H, Zhao M (2021) Inhibitory effect of osthole from Cnidium monnieri (L.) Cusson on Fusarium oxysporum, a common fungal pathogen of potato. Molecules 26(13):3818

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Neuberger A, Nadezhdin KD, Zakharian E, Sobolevsky AI (2021) Structural mechanism of TRPV3 channel inhibition by the plant-derived coumarin osthole. EMBO Rep 22(11):e53233

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Pan Z, Fang Z, Lu W, Liu X, Zhang Y (2015) Osthole, a coumadin analog from Cnidium monnieri (L.) Cusson, stimulates corticosterone secretion by increasing steroidogenic enzyme expression in mouse Y1 adrenocortical tumor cells. J Ethnopharmacol 175:456–462

    CAS  PubMed  Google Scholar 

  9. Shokoohinia Y, Bazargan S, Miraghaee S, Javadirad E, Farahani F, Hosseinzadeh L (2017) Safety assessment of osthole isolated from Prangos ferulacea: acute and subchronic toxicities and modulation of cytochrome P450. J Nat Pharm Prod 12(3)

  10. He H, Zhang Y, Zhao D, Jiang J, Xie B, Ma L, Liu X, Yu C (2020) Osthole inhibited the activity of CYP2C9 in human liver microsomes and influenced indomethacin pharmacokinetics in rats. Xenobiotica 50(8):939–946

    CAS  PubMed  Google Scholar 

  11. Lamptey RN, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J (2022) A review of the common neurodegenerative disorders: current therapeutic approaches and the potential role of nanotherapeutics. Int J Mol Sci 23:1851

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kovacs GG (2019) Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol 72:725–735

    CAS  PubMed  Google Scholar 

  13. Bagetta V, Ghiglieri V, Sgobio C, Calabresi P, Picconi B (2010) Synaptic dysfunction in Parkinson’s disease. Biochem Soc Trans 38:493–497

    CAS  PubMed  Google Scholar 

  14. Shao CY, Mirra SS, Sait HB, Sacktor TC, Sigurdsson EM (2011) Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced Aβ and tau pathology in transgenic mouse models of Alzheimer’s disease. Acta Neuropathol 122:285–292

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Cho SJ, Yun SM, Jo C, Jeong J, Park MH, Han C, Koh YH (2019) Altered expression of Notch1 in Alzheimer’s disease. PLoS ONE 14(11):e0224941

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Fumagalli F, Racagni G, Riva MA (2006) The expanding role of BDNF: a therapeutic target for Alzheimer’s disease. Pharmacogenomics J 6(1):8–15

    CAS  PubMed  Google Scholar 

  17. Howells DW, Porritt MJ, Wong JY, Batchelor PE, Kalnins R, Hughes AJ, Donnan GA (2000) Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 166(1):127–135

    CAS  PubMed  Google Scholar 

  18. Jurynczyk M, Selmaj K (2010) Notch: A new player in MS mechanisms. J Neuroimmunol 218(1–2):3–11

  19. Kowianski P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J (2018) BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol 38(3):579–593

  20. Sasi M, Vignoli B, Canossa M, Blum R (2017) Neurobiology of local and intercellular BDNF signaling. Pflügers Arch 469(5–6):593–610

    PubMed  PubMed Central  Google Scholar 

  21. Bloom GS (2014) Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508

    PubMed  Google Scholar 

  22. Wang J, Jing Y, Song L, Xing Y (2016) Neuroprotective effects of Wnt/β-catenin signaling pathway against Aβ-induced Tau protein over-phosphorylation in PC12 cells. Biochem Biophys Res Commun 471(4):628–632

    CAS  PubMed  Google Scholar 

  23. Kim T, Vidal GS, Djurisic M, William CM, Birnbaum ME, Garcia KC, Hyman BT, Shatz CJ (2013) Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science 341:1399–1404

    CAS  PubMed  Google Scholar 

  24. Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38:1205–1235

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang HY, Li W, Benedetti NJ, Lee DH (2003) α7 nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation. J Biol Chem 278:31547–31553

    CAS  PubMed  Google Scholar 

  26. Hashimoto Y, Kaneko Y, Tsukamoto E, Frankowski H, Kouyama K, Kita Y, Niikura T, Aiso S et al (2004) Molecular characterization of neurohybrid cell death induced by Alzheimer’s amyloid-β peptides via p75NTR/PLAIDD. J Neurochem 90:549–558

    CAS  PubMed  Google Scholar 

  27. Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, Avila J (2001) Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J 20(1–2):27–39

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Reddy PH (2013) Amyloid beta-induced glycogen synthase kinase 3β phosphorylated VDAC1 in Alzheimer’s disease: implications for synaptic dysfunction and neuronal damage. Biochimica et Biophysica Acta Mol. Basis Dis 12:1913–1921

    Google Scholar 

  29. Yun MS, Kim SE, Jeon SH, Lee JS, Choi KY (2005) Both ERK and Wnt/β-catenin pathways are involved in Wnt3a-induced proliferation. J Cell Sci 118(2):313–322

    CAS  PubMed  Google Scholar 

  30. Jia L, Piña-Crespo J, Li Y (2019) Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease. Mol Brain 12(1):104

    PubMed  PubMed Central  Google Scholar 

  31. Sun M, Sun M, Zhang J (2021) Osthole: an overview of its sources, biological activities, and modification development. Med Chem Res 30(10):1767–1794

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zafar S, Sarfraz I, Rasul A, Shah MA, Hussain G, Zahoor MK, Shafiq N, Riaz A et al (2021) Osthole: a multifunctional natural compound with potential anticancer, antioxidant and anti-inflammatory activities. Mini Rev Med Chem 21(18):2747–2763

    CAS  PubMed  Google Scholar 

  33. Zhang ZR, Leung WN, Cheung HY, Chan CW (2015) Osthole: a review on its bioactivities, pharmacological properties, and potential as alternative medicine. Evid Based Complement Alternat Med 2015:919616

    PubMed  PubMed Central  Google Scholar 

  34. Guan J, Wei X, Qu S, Lv T, Fu Q, Yuan Y (2017) Osthole prevents cerebral ischemia–reperfusion injury via the Notch signaling pathway. Biochem Cell Biol 95(4):459–467

    CAS  PubMed  Google Scholar 

  35. Chen T, Liu W, Chao X, Qu Y, Zhang L, Luo P, Xie K, Huo J et al (2011) Neuroprotective effect of osthole against oxygen and glucose deprivation in rat cortical neurons: involvement of mitogen-activated protein kinase pathway. J Neurosci 183:203–211

    CAS  Google Scholar 

  36. Yao Y, Gao Z, Liang W, Kong L, Jiao Y, Li S, Tao Z, Yan Y et al (2015) Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer’s disease model. Toxicol Appl Pharmacol 289(3):474–481

    CAS  PubMed  Google Scholar 

  37. Liu H, Xue X, Shi H, Qi L, Gong D (2015) Osthole upregulates BDNF to enhance adult hippocampal neurogenesis in APP/PS1 transgenic mice. Biol Pharm Bull 38(10):1439–1449

    CAS  PubMed  Google Scholar 

  38. Yan YH, Li SH, Li HY, Lin Y, Yang JX (2017) Osthole protects bone marrow-derived neural stem cells from oxidative damage through PI3K/Akt-1 pathway. Neurochem Res 42(2):398–405

    CAS  PubMed  Google Scholar 

  39. Kai K, Mizutani M, Kawamura N, Yamamoto R, Tamai M, Yamaguchi H, Sakata K, Shimizu BI (2008) Scopoletin is biosynthesized via ortho‐hydroxylation of feruloyl CoA by a 2‐oxoglutarate‐dependent dioxygenase in Arabidopsis thaliana. Plant J 55(6):989–99

  40. An SH, Choi GS, Ahn JH (2020) Biosynthesis of fraxetin from three different substrates using engineered Escherichia coli. Appl Biol Chem 63:55

    CAS  Google Scholar 

  41. Yang SM, Shim GY, Kim BG, Ahn JH (2015) Biological synthesis of coumarins in Escherichia coli. Microb Cell Factories 14:65

    Google Scholar 

  42. Parthasarathy A, Cross PJ, Dobson RCJ, Adams LE, Savka MA, Hudson AO (2018) A three-ring circus: metabolism of the three proteogenic aromatic amino acids and their role in the health of plants and animals. Front Mol Biosci 5:29

    PubMed  PubMed Central  Google Scholar 

  43. Sharma K, Zha J, Chouhan S, Guleria S, Koffas MA (2019) Biosynthesis of polyphenols in recombinant micro-organisms. Recent Adv Polyphenol Res 6:238

    Google Scholar 

  44. Shimizu BI (2014) 2-oxoglutarate-dependent dioxygenases in the biosynthesis of simple coumarins. Front Plant Sci 5:549

    PubMed  PubMed Central  Google Scholar 

  45. Liu DF, Ai GM, Zheng QX, Liu C, Jiang CY, Liu LX, Zhang B, Liu YM et al (2014) Metabolic flux responses to genetic modification for shikimic acid production by Bacillus subtilis strains. Microb Cell Factories 13(1):40

    Google Scholar 

  46. Mazimba O (2017) Umbelliferone: Sources, chemistry and bioactivities review. Bull Fac Pharm Cairo Univ 55:223–232

  47. Larbat R, Hehn A, Hans J, Schneider S, Jugdé H, Schneider B, Matern U, Bourgaud F (2009) Isolation and functional characterization of CYP71AJ4 encoding for the first P450 monooxygenase of angular furanocoumarin biosynthesis. J Biol Chem 284(8):4776–4785

    CAS  PubMed  Google Scholar 

  48. Karamat F, Olry A, Munakata R, Koeduka T, Sugiyama A, Paris C, Hehn A, Bourgaud F et al (2014) A coumarin-specific prenyltransferase catalyzes the crucial biosynthetic reaction for furanocoumarin formation in parsley. Plant J 77(4):627–638

    CAS  PubMed  Google Scholar 

  49. Cho PJ, Paudel S, Lee D, Jin YJ, Jo G, Jeong TC, Lee S, Lee T (2018) Characterization of CYPs and UGTs involved in human liver microsomal metabolism of osthenol. Pharmaceutics 10(3):141

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Baek SC, Kang MG, Park JE, Lee JP, Lee H, Ryu HW, Park CM, Park D et al (2019) Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity. Bioorg Med Chem Lett 29(6):839–843

    CAS  PubMed  Google Scholar 

  51. Totaro A, Castellan M, Di Biagio D, Piccolo S (2018) Crosstalk between YAP/TAZ and Notch signaling. Trends Cell Biol 28(7):560–573

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shen W, Huang J, Wang Y (2021) Biological significance of NOTCH signaling strength. Front Cell Dev Biol 9:652273

    PubMed  PubMed Central  Google Scholar 

  53. Brandstadter JD, Maillard I (2019) Notch signalling in T cell homeostasis and differentiation. Open Biol 9(11):190187

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Schwanbeck R (2015) The role of epigenetic mechanisms in Notch signaling during development. J Cell Physiol 230(5):969–981

  56. Yan Y, Kong L, Xia Y, Liang W, Wang L, Song J, Yao Y, Lin Y et al (2018) Osthole promotes endogenous neural stem cell proliferation and improved neurological function through Notch signaling pathway in mice acute mechanical brain injury. Brain Behav Immun 67:118–129

    CAS  PubMed  Google Scholar 

  57. Kong L, Hu Y, Yao Y, Jiao Y, Li S, Yang J (2015) The coumarin derivative osthole stimulates adult neural stem cells, promotes neurogenesis in the hippocampus, and ameliorates cognitive impairment in APP/PS1 transgenic mice. Biol Pharm Bull 38(9):1290–1301

    CAS  PubMed  Google Scholar 

  58. Rennert RC, Sorkin M, Garg RK, Gurtner GC (2012) Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med 7(6):833–850

    CAS  PubMed  Google Scholar 

  59. Rosso SB, Inestrosa NC (2013) WNT signaling in neuronal maturation and synaptogenesis. Front Cell Neurosci 7:103

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang L, Yan R, Su R, Yang C, Liu S, Yu X, Chang X, Zhang S et al (2014) Bioavailability enhancement of osthole after oral administration of Bushen Yizhi prescription extract to rats followed by Cnidium monnieri (L.) Cusson fruits extract in comparison to pure osthole at different doses. J Ethnopharmacol 152(2):266–271

    PubMed  Google Scholar 

  61. Zhang S, Li J, Lea R, Vleminckx K, Amaya E (2014) Fezf2 promotes neuronal differentiation through localised activation of Wnt/β-catenin signalling during forebrain development. Development 141(24):4794–4805

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Nusse R, Clevers H (2017) Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169(6):985–999

    CAS  PubMed  Google Scholar 

  63. L’episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B (2011) A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6:49

    PubMed  PubMed Central  Google Scholar 

  64. Chen S, Guttridge DC, You Z, Zhang Z, Fribley A, Mayo MW, Kitajewski J, Wang CY (2001) Wnt-1 signaling inhibits apoptosis by activating β-catenin/T cell factor–mediated transcription. J Cell Biol 152(1):87–96

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Su N, Wang P, Li Y (2016) Role of Wnt/β-catenin pathway in inducing autophagy and apoptosis in multiple myeloma cells. Oncol Lett 12(6):4623–4629

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang C, Liu S, Yuan X, Hu Z, Li H, Wu M, Yuan J, Zhao Z et al (2016) Valproic acid promotes human glioma U87 cells apoptosis and inhibits glycogen synthase kinase-3β through ERK/Akt signaling. Cell Physiol Biochem 39(6):2173–2185

    CAS  PubMed  Google Scholar 

  67. Li K, Ding D, Zhang M (2016) Neuroprotection of osthole against cerebral ischemia/reperfusion injury through an anti-apoptotic pathway in rats. Biol Pharm Bull 39(3):336–342

    CAS  PubMed  Google Scholar 

  68. He Y, Qu S, Wang J, He X, Lin W, Zhen H, Zhang X (2012) Neuroprotective effects of osthole pretreatment against traumatic brain injury in rats. Brain Res 1433:127–136

    CAS  PubMed  Google Scholar 

  69. Xiao H, Wang Y, Wu Y, Li H, Liang X, Lin Y, Kong L, Ni Y et al (2021) Osthole ameliorates cognitive impairments via augmenting neuronal population in APP/PS1 transgenic mice. Neurosci Res 164:33–45

    CAS  PubMed  Google Scholar 

  70. Liu WB, Zhou J, Qu Y, Li X, Lu CT, Xie KL, Sun XL, Fei Z (2010) Neuroprotective effect of osthole on MPP+-induced cytotoxicity in PC12 cells via inhibition of mitochondrial dysfunction and ROS production. Neurochem Int 57(3):206–215

    CAS  PubMed  Google Scholar 

  71. Lu H, Ma J, Luo Z, Huang Q, Zhang Y, Shi J (2017) Osthole attenuates early brain injury following subarachnoid hemorrhage in rats. Int J Clin Exp Med 10:10058–10065

    Google Scholar 

  72. Xia Y, Kong L, Yao Y, Jiao Y, Song J, Tao Z, You Z, Yang J (2015) Osthole confers neuroprotection against cortical stab wound injury and attenuates secondary brain injury. J Neuroinflammation 12:155

    PubMed  PubMed Central  Google Scholar 

  73. Moosavi F, Hosseini R, Saso L, Firuzi O (2016) Modulation of neurotrophic signaling pathways by polyphenols. Drug Des Dev Ther 10:23–42

    CAS  Google Scholar 

  74. Murphy KE, Park JJ (2017) Can co-activation of Nrf2 and neurotrophic signaling pathway slow Alzheimer’s disease? Int J Mol Sci 18(6):1168

    PubMed  PubMed Central  Google Scholar 

  75. Hannan MA, Dash R, Sohag AAM, Haque MN, Moon IS (2020) Neuroprotection against oxidative stress: phytochemicals targeting TrkB signaling and the Nrf2-ARE antioxidant system. Front Mol Neurosci 13:116

    PubMed  PubMed Central  Google Scholar 

  76. Chu Q, Zhu Y, Cao T, Zhang Y, Chang Z, Liu Y, Lu J, Zhang Y (2020) Studies on the neuroprotection of osthole on glutamate-induced apoptotic cells and an Alzheimer’s disease mouse model via modulation oxidative stress. Appl Biochem Biotechnol 190(2):634–644

    CAS  PubMed  Google Scholar 

  77. Hu Y, Wen Q, Liang W, Kang T, Ren L, Zhang N, Zhao D, Sun D et al (2013) Osthole reverses beta-amyloid peptide cytotoxicity on neural cells by enhancing cyclic AMP response element-binding protein phosphorylation. Biol Pharm Bull 36(12):1950–1958

    CAS  PubMed  Google Scholar 

  78. Yao Y, Wang Y, Kong L, Chen Y, Yang J (2019) Osthole decreases Tau protein phosphorylation via PI3K/AKT/GSK-3β signaling pathway in Alzheimer’s disease. Life Sci 217:16–24

    CAS  PubMed  Google Scholar 

  79. Tang H, Li K, Dou X, Zhao Y, Huang C, Shu F (2020) The neuroprotective effect of osthole against chronic sleep deprivation (CSD)-induced memory impairment in rats. Life Sci 263:118524

    CAS  PubMed  Google Scholar 

  80. Ji HJ, Hu JF, Wang YH, Chen XY, Zhou R, Chen NH (2010) Osthole improves chronic cerebral hypoperfusion induced cognitive deficits and neuronal damage in hippocampus. Eur J Pharmacol 636(1–3):96–101

    CAS  PubMed  Google Scholar 

  81. Jembrek MJ, Babić M, Pivac N, Hof PR, Šimić G (2013) Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: the interaction of Aβ and sphingolipid mediators as a therapeutic target. Transl Neurosci 4(4):466–476

    Google Scholar 

  82. Bao Y, Meng X, Liu F, Wang F, Yang J, Wang H, Xie G (2018) Protective effects of osthole against inflammation induced by lipopolysaccharide in BV2 cells. Mol Med Rep 17(3):4561–4566

    CAS  PubMed  Google Scholar 

  83. Chen Z, Mao X, Liu A, Gao X, Chen X, Ye M, Ye J, Liu P et al (2015) Osthole, a natural coumarin improves cognitive impairments and BBB dysfunction after transient global brain ischemia in C57 BL/6J mice: involvement of Nrf2 pathway. Neurochem Res 40(1):186–194

    CAS  PubMed  Google Scholar 

  84. Im HI, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35(5):325–334

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Martino S, Di Girolamo I, Orlacchio A, Datti A, Orlacchio A (2009) MicroRNA implications across neurodevelopment and neuropathology. J Biomed Biotechnol 2009:654346. https://doi.org/10.1155/2009/654346

  86. Coolen M, Katz S, Bally-Cuif L (2013) miR-9: a versatile regulator of neurogenesis. Front Cell Neurosci 7:220

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Meza-Sosa KF, Pedraza-Alva G, Pérez-Martínez L (2014) microRNAs: key triggers of neuronal cell fate. Front Cell Neurosci 8:175

    PubMed  PubMed Central  Google Scholar 

  88. Che H, Sun LH, Guo F, Niu HF, Su XL, Bao YN, Fu ZD, Liu HL et al (2014) Expression of amyloid-associated miRNAs in both the forebrain cortex and hippocampus of middle-aged rat. Cell Physiol Biochem 33(1):11–22

    CAS  PubMed  Google Scholar 

  89. Jiao Y, Kong L, Yao Y, Li S, Tao Z, Yan Y, Yang J (2016) Osthole decreases beta amyloid levels through up-regulation of miR-107 in Alzheimer’s disease. Neuropharmacology 108:332–344. https://doi.org/10.1016/j.neuropharm.2016.04.046

  90. Li SH, Gao P, Wang LT, Yan YH, Xia Y, Song J, Li HY, Yang JX (2017) Osthole stimulated neural stem cells differentiation into neurons in an Alzheimer’s disease cell model via upregulation of microRNA-9 and rescued the functional impairment of hippocampal neurons in APP/PS1 transgenic mice. Front Neurol 11:340

    Google Scholar 

  91. Ye Y, Xu H, Su X, He X (2016) Role of microRNA in governing synaptic plasticity. Neural Plast 2016

  92. Stein SC, Woods A, Jones NA, Davison MD, Carling D (2000) The regulation of AMP-activated protein kinase by phosphorylation. Biochem J 345(3):437–443

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Li S, Yan Y, Jiao Y, Gao Z, Xia Y, Kong L, Yao Y, Tao Z et al (2016) Neuroprotective effect of osthole on neuron synapses in an Alzheimer’s disease cell model via upregulation of microRNA-9. J Mol Neurosci 60(1):71–81

    CAS  PubMed  Google Scholar 

  94. Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F (2013) The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron 78(1):94–108

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Bachiller S, Jiménez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, Boza-Serrano A (2018) Microglia in neurological diseases: a road map to brain-disease dependent-inflammatory response. Front Cell Neurosci 12:488

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, Zaheer S, Iyer SS et al (2016) Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 1(1):1003

    PubMed  PubMed Central  Google Scholar 

  97. Chao X, Zhou J, Chen T, Liu W, Dong W, Qu Y, Jiang X, Ji X et al (2010) Neuroprotective effect of osthole against acute ischemic stroke on middle cerebral ischemia occlusion in rats. Brain Res 1363:206–211

    CAS  PubMed  Google Scholar 

  98. Li F, Gong Q, Wang L, Shi J (2012) Osthole attenuates focal inflammatory reaction following permanent middle cerebral artery occlusion in rats. Biol Pharm Bull 35(10):1686–1690

    CAS  PubMed  Google Scholar 

  99. Kong L, Yao Y, Xia Y, Liang X, Ni Y, Yang J (2019) Osthole alleviates inflammation by down-regulating NF-κB signaling pathway in traumatic brain injury. Immunopharmacol Immunotoxicol 41(2):349–360

    CAS  PubMed  Google Scholar 

  100. Dorrington MG, Fraser IDC (2019) NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Front Immunol 10:705

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Liao PC, Chien SC, Ho CL, Wang EI, Lee SC, Kuo YH, Jeyashoke N, Chen J et al (2010) Osthole regulates inflammatory mediator expression through modulating NF-κB, mitogen-activated protein kinases, protein kinase C, and reactive oxygen species. J Agric Food Chem 58(19):10445–10451

    CAS  PubMed  Google Scholar 

  102. Guo H, Callaway JB, Ting JP (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med 21(7):677–687

    PubMed  PubMed Central  Google Scholar 

  103. Liu Y, Chen X, Gong Q, Shi J, Li F (2020) Osthole improves cognitive function of vascular dementia rats: reducing Aβ deposition via inhibition NLRP3 inflammasome. Biol Pharm Bull 43(9):1315–1323

    CAS  PubMed  Google Scholar 

  104. Song Y, Wang X, Wang X, Wang J, Hao Q, Hao J, Hou X (2021) Osthole-loaded nanoemulsion enhances brain target in the treatment of Alzheimer’s disease via intranasal administration. Oxid Med Cell Longev 2021:8844455. https://doi.org/10.1155/2021/8844455

  105. Hou X, Xu L, Liu X, Zhang HT (2020) Effects of osthole microemulsion by nasal administration on the cholinergic pathway in mice treated with scopolamine. FASEB J 34(S1):1–1

    Google Scholar 

  106. Gao S, Hu M (2010) Bioavailability challenges associated with development of anti-cancer phenolics. Mini Rev Med Chem 10(6):550–567

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Kesarwani K, Gupta R (2013) Bioavailability enhancers of herbal origin: an overview. Asian Pac J Trop Biomed 3(4):253–266

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Aqil F, Munagala R, Jeyabalan J, Vadhanam MV (2013) Bioavailability of phytochemicals and its enhancement by drug delivery systems. Cancer Lett 334(1):133–141. https://doi.org/10.1016/j.canlet.2013.02.032

  109. Li LP, Wang XJ, Zhang JY, Zhang LL, Cao YB, Gu LQ, Yu YQ, Yang QL et al (2018) Antifungal activity of osthol in vitro and enhancement in vivo through Eudragit S100 nanocarriers. Virulence 9(1):555–562

    CAS  PubMed  Google Scholar 

  110. Gitler AD, Dhillon P, Shorter J (2017) Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech 10(5):499–502

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Sheikh S, Safia HE, Haque E, Mir SS (2013) Neurodegenerative diseases: multifactorial conformational diseases and their therapeutic interventions. J Neurodegener Dis 563481

  112. Kovacs GG (2014) Current concepts of neurodegenerative diseases. EMJ Neurol 1:78–86

    Google Scholar 

  113. Horgusluoglu E, Nudelman K, Nho K, Saykin AJ (2017) Adult neurogenesis and neurodegenerative diseases: a systems biology perspective. Am J Med Genet B Neuropsychiatr Genet 174(1):93–112

    CAS  PubMed  Google Scholar 

  114. Palop JJ, Chin J, Mucke L (2006) A network dysfunction perspective on neurodegenerative diseases. Nature 443(7113):768–773

    CAS  PubMed  Google Scholar 

  115. Gómez-Pinedo U, Galán L, Matías-Guiu JA, Pytel V, Moreno T, Guerrero-Sola A, Matías-Guiu J (2019) Notch signalling in the hippocampus of patients with motor neuron disease. Front Neurosci 13:302

    PubMed  PubMed Central  Google Scholar 

  116. Chojnacki A, Shimazaki T, Gregg C, Weinmaster G, Weiss S (2003) Glycoprotein 130 signaling regulates notch1expression and activation in the self-renewal of mammalian forebrain neural stem cells. J Neurosci 23(5):1730–1741

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Alberi L, Hoey SE, Brai E, Scotti AL, Marathe S (2013) Notch signaling in the brain: in good and bad times. Ageing Res Rev 12(3):801–814

    CAS  PubMed  Google Scholar 

  118. Marathe S, Jaquet M, Annoni JM, Alberi L (2017) Jagged1 is altered in Alzheimer’s disease and regulates spatial memory processing. Front Cell Neurosci 11:220

    PubMed  PubMed Central  Google Scholar 

  119. Presente A, Boyles RS, Serway CN, de Belle JS, Andres AJ (2004) Notch is required for long-term memory in Drosophila. Proc Natl Acad Sci USA 101(6):1764–1768

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Chen WW, Zhang XI, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13(4):3391–3396

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Jeong JW, Jin CY, Kim GY, Lee JD, Park C, Kim GD, Kim WJ, Jung WK et al (2010) Antiinflammatory effects of cordycepin via suppression of inflammatory mediators in BV2 microglial cells. Int Immunopharmacol 10(12):1580–1586

    CAS  PubMed  Google Scholar 

  122. Murray PS, Holmes PV (2011) An overview of brain-derived neurotrophic factor and implications for excitotoxic vulnerability in the hippocampus. Int J Pept 654085

  123. Danzer SC, Crooks KR, Lo DC, McNamara JO (2002) Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures. J Neurosci 22(22):9754–9763

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192(2):348–356

    CAS  PubMed  Google Scholar 

  125. Zu G, Guo J, Che N, Zhou T, Zhang X, Wang G, Ji TX, Tian X (2016) Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway. Sci Rep 6:38480

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Shi ZY, Deng JX, Fu S, Wang L, Wang Q, Liu B, Li YQ, Deng JB (2017) Protective effect of autophagy in neural ischemia and hypoxia: negative regulation of the Wnt/β-catenin pathway. Int J Mol Med 40(6):1699–1708

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Llorens-Martín M, Jurado J, Hernández F, Ávila J (2014) GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci 7:46

    PubMed  Google Scholar 

  128. Pinheiro L, Faustino C (2019) Therapeutic strategies targeting amyloid-β in Alzheimer’s disease. Curr Alzheimer Res 16(5):418–452

    CAS  PubMed  Google Scholar 

  129. Huang LK, Chao SP, Hu CJ (2020) Clinical trials of new drugs for Alzheimer disease. J Biomed Sci 27(1):1–13

    Google Scholar 

  130. Goedert M, Spillantini MG, Crowther RA (1991) Tau proteins and neurofibrillary degeneration. Brain Pathol 1(4):279–286

    CAS  PubMed  Google Scholar 

  131. Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J (2007) Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol 152(6):959–979

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Eldar-Finkelman H, Martinez A (2011) GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci 4:32

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L (2017) The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy. Int J Mol Med 40(2):271–280

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the facilities provided by Guru Nanak Dev University in carrying out the literature survey for the current work.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, Punjab, India

    Lovedeep Singh & Rajbir Bhatti

  2. University Institute of Pharma Sciences, Chandigarh University, Mohali, 140413, Punjab, India

    Lovedeep Singh

Authors
  1. Lovedeep Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajbir Bhatti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.S. carried out the literature survey and wrote the manuscript. R.B. has conceptualized and designed the idea and done language editing.

Corresponding authors

Correspondence to Lovedeep Singh or Rajbir Bhatti.

Ethics declarations

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

Not applicable.

Consent for Publication

Not applicable

Conflict of Interest

The authors declare no competing interests.

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

Singh, L., Bhatti, R. Signaling Pathways Involved in the Neuroprotective Effect of Osthole: Evidence and Mechanisms. Mol Neurobiol 61, 1100–1118 (2024). https://doi.org/10.1007/s12035-023-03580-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-023-03580-9

Keywords

Search

Navigation