Skip to main content

Advertisement

SpringerLink
Log in

Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Schizophrenia (SZ) is a chronic psychiatric disorder affecting several people worldwide. Mitochondrial DNA (mtDNA) variations could invoke changes in the OXPHOS system, calcium buffering, and ROS production, which have significant implications for glial cell survival during SZ. Oxidative stress has been implicated in glial cells-mediated pathogenesis of SZ; the brain comparatively more prone to oxidative damage through NMDAR. A confluence of scientific evidence points to mtDNA alterations, Nrf2 signaling, dynamic alterations in dorsolateral prefrontal cortex (DLPFC), and provocation of oxidative stress that enhance pathophysiology of SZ. Furthermore, the alterations in excitatory signaling related to NMDAR signaling were particularly reported for SZ pathophysiology. Current review reported the recent evidence for the role of mtDNA variations and oxidative stress in relation to pathophysiology of SZ, NMDAR hypofunction, and glutathione deficiency. NMDAR system is influenced by redox dysregulation in oxidative stress, inflammation, and antioxidant mediators. Several studies have demonstrated the relationship of these variables on severity of pathophysiology in SZ. An extensive literature search was conducted using Medline, PubMed, PsycINFO, CINAHL PLUS, BIOSIS Preview, Google scholar, and Cochrane databases. We summarize consistent evidence pointing out a plausible model that may elucidate the crosstalk between mtDNA alterations in glial cells and redox dysregulation during oxidative stress and the perturbation of NMDA neurotransmitter system during current therapeutic modalities for the SZ treatment. This review can be beneficial for the development of promising novel diagnostics, and therapeutic modalities by ascertaining the mtDNA variations, redox state, and efficacy of pharmacological agents to mitigate redox dysregulation and augment NMDAR function to treat cognitive and behavioral symptoms in SZ.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

Not applicable.

Abbreviations

LARS2:

Leucyl-tRNA synthetase

GAPDH:

Glyceralde-hyde-3-phosphate dehydrogenase

ETC:

Electron transport chain

AMPK:

AMP-activated protein kinase

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha

DLPFC:

Dorsolateral prefrontal cortex

mtSNPs:

Mitochondrial single nucleotide polymorphism

PFC:

Prefrontal cortex

GCLM:

Glutamate cysteine ligase

GRIN2A:

Glutamate ionotropic receptor NMDA type subunit 2A

Disc1:

Disrupted-in-schizophrenia 1

NDUFV1:

NADH:ubiquinone oxidoreductase core subunit V1

HSP:

Heat shock protein

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha

NF-kB:

Nuclear factor–kappa B

TNF-α:

Tumor necrotic factor–α

ETC:

Electron transport chain

GSTT-2:

Glutathione S-transferase theta 2

GAD67:

Glutamic acid decarboxylase 67

References

  1. Kondej M, Stępnicki P, Kaczor AA (2018) Multi-target approach for drug discovery against schizophrenia. Int J Mol Sci 19(10):3105

    Article  PubMed Central  Google Scholar 

  2. Bitanihirwe BK, Woo T-UW (2011) Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev 35(3):878–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M (2015) Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48:10–21

    Article  CAS  PubMed  Google Scholar 

  4. Adell A (2020) Brain NMDA receptors in schizophrenia and depression. Biomolecules 10(6):947

    Article  CAS  PubMed Central  Google Scholar 

  5. Inan M, Petros TJ, Anderson SA (2013) Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia. Neurobiol Dis 53:36–48

    Article  CAS  PubMed  Google Scholar 

  6. Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M (2009) Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol 19(2):220–230

    Article  CAS  PubMed  Google Scholar 

  7. Wood SJ, Yücel M, Pantelis C, Berk M (2009) Neurobiology of schizophrenia spectrum disorders: the role of oxidative stress. Ann Acad Med Singapore 38(5):396–401

    Article  PubMed  Google Scholar 

  8. Yao JK, Reddy RD, Van Kammen DP (2001) Oxidative damage and schizophrenia. CNS Drugs 15(4):287–310

    Article  CAS  PubMed  Google Scholar 

  9. Yao JK, Leonard S, Reddy RD (2004) Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr Bull 30(4):923–934

    Article  PubMed  Google Scholar 

  10. Yao JK, Leonard S, Reddy R (2006) Altered glutathione redox state in schizophrenia. Dis Markers 22(1–2):83–93

    Article  CAS  PubMed  Google Scholar 

  11. Yao J, Dougherty G, Reddy R, Keshavan M, Montrose D, Matson W, Rozen S, Krishnan R et al (2010) Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol Psychiatry 15(9):938–953

    Article  CAS  PubMed  Google Scholar 

  12. Matsuzawa D, Hashimoto K (2011) Magnetic resonance spectroscopy study of the antioxidant defense system in schizophrenia. Antioxid Redox Signal 15(7):2057–2065

    Article  CAS  PubMed  Google Scholar 

  13. Zhang M, Zhao Z, He L, Wan C (2010) A meta-analysis of oxidative stress markers in schizophrenia. Sci China Life Sci 53(1):112–124

    Article  CAS  PubMed  Google Scholar 

  14. Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44(7):660–669

    Article  CAS  PubMed  Google Scholar 

  15. Lewis DA, Lieberman JA (2000) Catching up on schizophrenia: natural history and neurobiology. Neuron 28(2):325–334

    Article  CAS  PubMed  Google Scholar 

  16. Lewis DA, Levitt P (2002) Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25(1):409–432

    Article  CAS  PubMed  Google Scholar 

  17. Sawa A, Snyder SH (2002) Schizophrenia: diverse approaches to a complex disease. Science 296(5568):692–695

    Article  CAS  PubMed  Google Scholar 

  18. Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A (2009) Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1–ErbB4 and DISC1. Trends Neurosci 32(9):485–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10(1):40–68

    Article  CAS  PubMed  Google Scholar 

  20. Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528–548

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rampino A, Marakhovskaia A, Soares-Silva T, Torretta S, Veneziani F, Beaulieu JM (2019) Antipsychotic drug responsiveness and dopamine receptor signaling; old players and new prospects. Front Psych 9:702

    Article  Google Scholar 

  22. Hashimoto K (2014) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets 18(9):1049–1063

    Article  CAS  PubMed  Google Scholar 

  23. Goldsmith CAW, Rogers DP (2008) The case for autoimmunity in the etiology of schizophrenia. Pharmacotherapy 28(6):730–741

    Article  CAS  PubMed  Google Scholar 

  24. Laskaris L, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, Cropley VL, Pantelis C (2016) Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol 173(4):666–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Horrobin DF, Glen A, Hudson CJ (1995) Possible relevance of phospholipid abnormalities and genetic interactions in psychiatric disorders: the relationship between dyslexia and schizophrenia. Med Hypotheses 45(6):605–613

    Article  CAS  PubMed  Google Scholar 

  26. Murray AJ, Rogers JC, Katshu MZUH, Liddle PF, Upthegrove R (2021) Oxidative stress and the pathophysiology and symptom profile of schizophrenia spectrum disorders. Frontiers in Psychiatry 1235(12)

  27. Clay HB, Sillivan S, Konradi C (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 29(3):311–324

    Article  CAS  PubMed  Google Scholar 

  28. Amar S, Shamir A, Ovadia O, Blanaru M, Reshef A, Kremer I, Rietschel M, Schulze TG et al (2007) Mitochondrial DNA HV lineage increases the susceptibility to schizophrenia among Israeli Arabs. Schizophr Res 94(1–3):354–358

    Article  PubMed  Google Scholar 

  29. Marchbanks R, Ryan M, Day I, Owen M, McGuffin P, Whatley S (2003) A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress. Schizophr Res 65(1):33–38

    Article  CAS  PubMed  Google Scholar 

  30. Rollins B, Martin MV, Sequeira PA, Moon EA, Morgan LZ, Watson SJ, Schatzberg A, Akil H, Myers RM et al (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PloS One 4(3):e4913

    Article  PubMed  PubMed Central  Google Scholar 

  31. Verge B, Alonso Y, Valero J, Miralles C, Vilella E, Martorell L (2011) Mitochondrial DNA (mtDNA) and schizophrenia. Eur Psychiatry 26(1):45–56

    Article  CAS  PubMed  Google Scholar 

  32. Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y, Young TA, Bullard J et al (2005) Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiat 58(2):85–96

    Article  CAS  PubMed  Google Scholar 

  33. Iwamoto K, Bundo M, Kato T (2005) Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 14(2):241–253

    Article  CAS  PubMed  Google Scholar 

  34. Ben-Shachar D, Karry R (2008) Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression. PloS One 3(11):e3676

    Article  PubMed  PubMed Central  Google Scholar 

  35. Karry R, Klein E, Shachar DB (2004) Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study. Biol Psychiat 55(7):676–684

    Article  CAS  PubMed  Google Scholar 

  36. Da Silva T, Wu A, Laksono I, Prce I, Maheandiran M, Kiang M, Andreazza AC, Mizrahi R (2018) Mitochondrial function in individuals at clinical high risk for psychosis. Sci Rep 8(1):1–10

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125(7):1241–1252

    Article  CAS  PubMed  Google Scholar 

  38. Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60(5):748–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ben-Shachar D, Laifenfeld D (2004) Mitochondria, synaptic plasticity, and schizophrenia. In: International review of neurobiology, vol 59. Elsevier, pp 273–296

  40. Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, Jones EG, Bunney WE et al (2008) Mitochondrial involvement in psychiatric disorders. Ann Med 40(4):281–295

    Article  CAS  PubMed  Google Scholar 

  41. Bulygin KV, Beeraka NM, Saitgareeva AR, Nikolenko VN, Gareev I, Beylerli O, Akhmadeeva LR, Mikhaleva LM et al (2020) Can miRNAs be considered as diagnostic and therapeutic molecules in ischemic stroke pathogenesis?—Current status. Int J Mol Sci 21(18):6728

    Article  CAS  PubMed Central  Google Scholar 

  42. Prayson RA, Wang N (1998) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch Pathol Lab Med 122(11):978

    CAS  PubMed  Google Scholar 

  43. Millar J, Christie S, Anderson S, Lawson D, Loh DH-W, Devon R, Arveiler B, Muir W et al (2001) Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. Mol Psychiatry 6(2):173–178

    Article  CAS  PubMed  Google Scholar 

  44. Sachs N, Sawa A, Holmes S, Ross C, DeLisi L, Margolis R (2005) A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry 10(8):758–764

    Article  CAS  PubMed  Google Scholar 

  45. Porteous DJ, Thomson P, Millar JK, Evans KL, Hennah W, Soares D, McCarthy S, McCombie W et al (2014) DISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan. Mol Psychiatry 19(2):141–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sullivan PF (2013) Questions about DISC1 as a genetic risk factor for schizophrenia. Mol Psychiatry 18(10):1050–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brandon NJ, Millar JK, Korth C, Sive H, Singh KK, Sawa A (2009) Understanding the role of DISC1 in psychiatric disease and during normal development. J Neurosci 29(41):12768–12775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chubb J, Bradshaw NJ, Soares D, Porteous D, Millar J (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13(1):36–64

    Article  CAS  PubMed  Google Scholar 

  49. Martorell L, Segués T, Folch G, Valero J, Joven J, Labad A, Vilella E (2006) New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14(5):520–528

    Article  CAS  PubMed  Google Scholar 

  50. Whatley S, Curti D, Gupta FD, Ferrier I, Jones S, Taylor C, Marchbanks R (1998) Superoxide, neuroleptics and the ubiquinone and cytochrome b 5 reductases in brain and lymphocytes from normals and schizophrenic patients. Mol Psychiatry 3(3):227–237

    Article  CAS  PubMed  Google Scholar 

  51. Dröge W, Schipper HM (2007) Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6(3):361–370

    Article  PubMed  Google Scholar 

  52. Parikh V, Khan MM, Mahadik SP (2003) Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 37(1):43–51

    Article  PubMed  Google Scholar 

  53. Kazuno A-a, Munakata K, Nagai T, Shimozono S, Tanaka M, Yoneda M, Kato N, Miyawaki A et al (2006) Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet 2(8):e128

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ueno H, Nishigaki Y, Kong Q-P, Fuku N, Kojima S, Iwata N, Ozaki N, Tanaka M (2009) Analysis of mitochondrial DNA variants in Japanese patients with schizophrenia. Mitochondrion 9(6):385–393

    Article  CAS  PubMed  Google Scholar 

  55. Munakata K, Iwamoto K, Bundo M, Kato T (2005) Mitochondrial DNA 3243A> G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia. Biol Psychiat 57(5):525–532

    Article  CAS  PubMed  Google Scholar 

  56. Ni P, Chung S (2020) Mitochondrial dysfunction in schizophrenia. BioEssays 42(6):1900202

    Article  Google Scholar 

  57. Park C, Park SK (2012) Molecular links between mitochondrial dysfunctions and schizophrenia. Mol Cells 33(2):105–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Martins-de-Souza D, Harris LW, Guest PC, Bahn S (2011) The role of energy metabolism dysfunction and oxidative stress in schizophrenia revealed by proteomics. Antioxid Redox Signal 15(7):2067–2079

    Article  CAS  PubMed  Google Scholar 

  59. Martins-de-Souza D, Gattaz WF, Dias-Neto E (2011) What does proteomics tell us about schizophrenia? In: Handbook of Schizophrenia Spectrum Disorders, Volume I. Springer, pp 345–366

  60. Prabakaran S, Swatton J, Ryan M, Huffaker S, Huang J-J, Griffin J, Wayland M, Freeman T et al (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9(7):684–697

    Article  CAS  PubMed  Google Scholar 

  61. Maas D, Vallès A, Martens G (2017) Oxidative stress, prefrontal cortex hypomyelination and cognitive symptoms in schizophrenia. Transl Psychiatry 7(7):e1171–e1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bonora M, De Marchi E, Patergnani S, Suski J, Celsi F, Bononi A, Giorgi C, Marchi S et al (2014) Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process. Cell Death Differ 21(8):1198–1208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zou Y, Jiang W, Wang J, Li Z, Zhang J, Bu J, Zou J, Zhou L et al (2014) Oligodendrocyte precursor cell-intrinsic effect of Rheb1 controls differentiation and mediates mTORC1-dependent myelination in brain. J Neurosci 34(47):15764–15778

    Article  PubMed  PubMed Central  Google Scholar 

  64. Cao K, Zheng A, Xu J, Li H, Liu J, Peng Y, Long J, Zou X et al (2014) AMPK activation prevents prenatal stress-induced cognitive impairment: modulation of mitochondrial content and oxidative stress. Free Radical Biol Med 75:156–166

    Article  CAS  Google Scholar 

  65. Chen Y, Lu R, Zheng H, Xiao R, Feng J, Wang H, Gao X, Guo L (2015) The NFKB1 polymorphism (rs4648068) is associated with the cell proliferation and motility in gastric cancer. BMC Gastroenterol 15(1):21

    Article  PubMed  PubMed Central  Google Scholar 

  66. Glauert HP, Calfee-Mason K, Li Y, Nilakantan V, Twaroski ML, Tharappel J, Spear BT (2008) The role of NF-κB in PPARα-mediated hepatocarcinogenesis. Ppar Research 2008:286249

  67. Li Y, Beeraka NM, Guo W, Lei Y, Hu Q, Guo L, Fan R, Liu J, et al (2021) Prognosis of patients with brainstem glioblastoma based on ‘age, surgery and radiotherapy’: a SEER database analysis

  68. Nikolenko VN, Rizaeva NA, Beeraka NM, Oganesyan MV, Kudryashova VA, Dubovets AA, Borminskaya ID, Bulygin KV et al (2021) The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology. Behav Brain Funct 17(1):1–10

    Article  Google Scholar 

  69. Shen Q, Li Z, Sun Y, Wang T, Wan C, Li X, Zhao X, Feng G et al (2008) The role of pro-inflammatory factors in mediating the effects on the fetus of prenatal undernutrition: implications for schizophrenia. Schizophr Res 99(1–3):48–55

    Article  CAS  PubMed  Google Scholar 

  70. Diz-Chaves Y, Astiz M, Bellini MJ, Garcia-Segura LM (2013) Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice. Brain Behav Immun 28:196–206

    Article  CAS  PubMed  Google Scholar 

  71. Feigenson KA, Kusnecov AW, Silverstein SM (2014) Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev 38:72–93

    Article  PubMed  Google Scholar 

  72. Abi-Saab W, D’souza D, Moghaddam B, Krystal J (1998) The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 31(S2):104–109

    Article  CAS  PubMed  Google Scholar 

  73. Rolland B, Jardri R, Amad A, Thomas P, Cottencin O, Bordet R (2014) Pharmacology of hallucinations: several mechanisms for one single symptom? BioMed Res Int

  74. Coyle JT (2012) NMDA receptor and schizophrenia: a brief history. Schizophr Bull 38(5):920–926

    Article  PubMed  PubMed Central  Google Scholar 

  75. Rolland B, Jardri R, Amad A, Thomas P, Cottencin O, Bordet R (2014) Pharmacology of hallucinations: several mechanisms for one single symptom? BioMed Research International 2014:307106

  76. Goldsmith DR, Rapaport MH (2020) Inflammation and negative symptoms of schizophrenia: Implications for reward processing and motivational deficits. Frontiers in Psychiatry 11:46

  77. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51(3):199–214

    Article  CAS  PubMed  Google Scholar 

  78. Lahti AC, Weiler MA, Michaelidis BT, Parwani A, Tamminga CA (2001) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25(4):455–467

    Article  CAS  PubMed  Google Scholar 

  79. Hardingham GE, Do KQ (2016) Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis. Nat Rev Neurosci 17(2):125–134

    Article  CAS  PubMed  Google Scholar 

  80. Dogan AE, Yuksel C, Du F, Chouinard V-A, Öngür D (2018) Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies. Neuropsychopharmacology 43(8):1681–1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bergen SE, Petryshen TL (2012) Genome-wide association studies (GWAS) of schizophrenia: does bigger lead to better results? Curr Opin Psychiatry 25(2):76

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ripke S, Neale BM, Corvin A, Walters JT, Farh K-H, Holmans PA, Lee P, Bulik-Sullivan B et al (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421

    Article  CAS  PubMed Central  Google Scholar 

  83. Aliev G, Beeraka NM, Nikolenko VN, Svistunov AA, Rozhnova T, Kostyuk S, Cherkesov I, Gavryushova LV et al (2020) Neurophysiology and psychopathology underlying PTSD and recent insights into the PTSD therapies—a comprehensive review. J Clin Med 9(9):2951

    Article  CAS  PubMed Central  Google Scholar 

  84. Balu DT (2016) The NMDA receptor and schizophrenia: from pathophysiology to treatment. In: Advances in Pharmacology, vol 76. Elsevier, pp 351–382

  85. Coyle JT, Balu D, Benneyworth M, Basu A, Roseman A (2010) Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia. Dialogues Clin Neurosci 12(3):359

    Article  PubMed  PubMed Central  Google Scholar 

  86. Schmidt-Kastner R, Guloksuz S, Kietzmann T, Van Os J, Rutten BP (2020) Analysis of GWAS-derived schizophrenia genes for links to ischemia-hypoxia response of the brain. Front Psych 11:393

    Article  Google Scholar 

  87. Bitanihirwe BK, Mauney SA, Woo T-UW (2016) Weaving a net of neurobiological mechanisms in schizophrenia and unraveling the underlying pathophysiology. Biol Psychiat 80(8):589–598

    Article  PubMed  Google Scholar 

  88. Goff DC, Romero K, Paul J, Perez-Rodriguez MM, Crandall D, Potkin SG (2016) Biomarkers for drug development in early psychosis: current issues and promising directions. Eur Neuropsychopharmacol 26(6):923–937

    Article  CAS  PubMed  Google Scholar 

  89. Noto C, Ota VK, Gadelha A, Noto MN, Barbosa DS, Bonifácio KL, Nunes SO, Cordeiro Q et al (2015) Oxidative stress in drug naïve first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res 68:210–216

    Article  PubMed  Google Scholar 

  90. Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry 48(6):512–529

    Article  PubMed  Google Scholar 

  91. Gallego JA, Blanco EA, Husain-Krautter S, Fagen EM, Moreno-Merino P, del Ojo-Jiménez JA, Ahmed A, Rothstein TL et al (2018) Cytokines in cerebrospinal fluid of patients with schizophrenia spectrum disorders: new data and an updated meta-analysis. Schizophr Res 202:64–71

    Article  PubMed  PubMed Central  Google Scholar 

  92. Garver DL, Tamas RL, Holcomb JA (2003) Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology 28(8):1515–1520

    Article  CAS  PubMed  Google Scholar 

  93. O’Rourke R, Kay T, Lyle E, Traxler S, Deveney C, Jobe B, Roberts C Jr, Marks D et al (2006) Alterations in peripheral blood lymphocyte cytokine expression in obesity. Clin Exp Immunol 146(1):39–46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chase KA, Cone JJ, Rosen C, Sharma RP (2016) The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia. BMC Psychiatry 16(1):1–7

    Article  Google Scholar 

  95. Jordan W, Dobrowolny H, Bahn S, Bernstein H-G, Brigadski T, Frodl T, Isermann B, Lessmann V et al (2018) Oxidative stress in drug-naïve first episode patients with schizophrenia and major depression: effects of disease acuity and potential confounders. Eur Arch Psychiatry Clin Neurosci 268(2):129–143

    Article  PubMed  Google Scholar 

  96. Dwir D, Giangreco B, Xin L, Tenenbaum L, Cabungcal J-H, Steullet P, Goupil A, Cleusix M, Jenni R, Baumann PS (2019) MMP9/RAGE pathway overactivation mediates redox dysregulation and neuroinflammation, leading to inhibitory/excitatory imbalance: a reverse translation study in schizophrenia patients. Molecular psychiatry 25(11):2889–2904

  97. Sarandol A, Kirli S, Akkaya C, Altin A, Demirci M, Sarandol E (2007) Oxidative–antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: effects of short term antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatry 31(6):1164–1169

    Article  CAS  PubMed  Google Scholar 

  98. Liu M-L, Zheng P, Liu Z, Xu Y, Mu J, Guo J, Huang T, Meng H-Q et al (2014) GC-MS based metabolomics identification of possible novel biomarkers for schizophrenia in peripheral blood mononuclear cells. Mol BioSyst 10(9):2398–2406

    Article  CAS  PubMed  Google Scholar 

  99. Kim S-Y, Cohen BM, Chen X, Lukas SE, Shinn AK, Yuksel AC, Li T, Du F et al (2017) Redox dysregulation in schizophrenia revealed by in vivo NAD+/NADH measurement. Schizophr Bull 43(1):197–204

    Article  PubMed  Google Scholar 

  100. Copoglu US, Virit O, Kokacya MH, Orkmez M, Bulbul F, Erbagci AB, Semiz M, Alpak G et al (2015) Increased oxidative stress and oxidative DNA damage in non-remission schizophrenia patients. Psychiatry Res 229(1–2):200–205

    Article  Google Scholar 

  101. Lijuan Huo XL, Fengchun Wu, Chang C, Ning Y, Zhang XY (November 2021) Elevated activity of superoxide dismutase in male late-life schizophrenia and its correlation with clinical symptoms and cognitive deficits. BMC Psychiatry 21:606

    Article  PubMed  PubMed Central  Google Scholar 

  102. Đorđević VV, Lazarević D, Ćosić V, Knežević MZ, Đorđević VB (2017) Age-related changes of superoxide dismutase activity in patients with schizophrenia. Vojnosanit Pregl 74(1):31–37

    Article  PubMed  Google Scholar 

  103. Radonjić NV, Knežević ID, Vilimanovich U, Kravić-Stevović T, Marina LV, Nikolić T, Todorović V, Bumbaširević V et al (2010) Decreased glutathione levels and altered antioxidant defense in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration. Neuropharmacology 58(4–5):739–745

    Article  PubMed  Google Scholar 

  104. Reddy R, Keshavan M, Yao JK (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 62(3):205–212

    Article  PubMed  Google Scholar 

  105. Ohnuma T, Nishimon S, Takeda M, Sannohe T, Katsuta N, Arai H (2018) Carbonyl stress and microinflammation-related molecules as potential biomarkers in schizophrenia. Front Psych 9:82

    Article  Google Scholar 

  106. Noto C, Maes M, Ota VK, Teixeira AL, Bressan RA, Gadelha A, Brietzke E (2015) High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. The World Journal of Biological Psychiatry 16(6):422–429

    Article  PubMed  Google Scholar 

  107. Noto C, Gadelha A, Belangero SI, Spindola LM, Rocha NP, de Miranda AS, Teixeira AL, Smith MAC et al (2013) Circulating levels of sTNFR1 as a marker of severe clinical course in schizophrenia. J Psychiatr Res 47(4):467–471

    Article  PubMed  Google Scholar 

  108. Nishimon S, Ohnuma T, Takebayashi Y, Katsuta N, Takeda M, Nakamura T, Sannohe T, Higashiyama R et al (2017) High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 76:145–154

    Article  CAS  PubMed  Google Scholar 

  109. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, Pollmächer T (1999) Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 33(5):407–418

    Article  CAS  PubMed  Google Scholar 

  110. Cuenod M, Steullet P, Cabungcal J-H, Dwir D, Khadimallah I, Klauser P, Conus P, Do KQ (2021) Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia. Molecular Psychiatry 1–12

  111. Pérez-Santiago J, Diez-Alarcia R, Callado LF, Zhang JX, Chana G, White CH, Glatt SJ, Tsuang MT et al (2012) A combined analysis of microarray gene expression studies of the human prefrontal cortex identifies genes implicated in schizophrenia. J Psychiatr Res 46(11):1464–1474

    Article  PubMed  Google Scholar 

  112. Karagiannis A, Gallopin T, Dávid C, Battaglia D, Geoffroy H, Rossier J, Hillman EM, Staiger JF et al (2009) Classification of NPY-expressing neocortical interneurons. J Neurosci 29(11):3642–3659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kubota Y (2014) Untangling GABAergic wiring in the cortical microcircuit. Curr Opin Neurobiol 26:7–14

    Article  CAS  PubMed  Google Scholar 

  114. Tremblay R, Lee S, Rudy B (2016) GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron 91(2):260–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Vruwink M, Schmidt HH, Weinberg RJ, Burette A (2001) Substance P and nitric oxide signaling in cerebral cortex: anatomical evidence for reciprocal signaling between two classes of interneurons. Journal of Comparative Neurology 441(4):288–301

    Article  CAS  Google Scholar 

  116. Bowen EF, Burgess JL, Granger R, Kleinman JE, Rhodes CH (2019) DLPFC transcriptome defines two molecular subtypes of schizophrenia. Transl Psychiatry 9(1):1–10

    CAS  Google Scholar 

  117. Cardis R, Cabungcal J-H, Dwir D, Do KQ, Steullet P (2018) A lack of GluN2A-containing NMDA receptors confers a vulnerability to redox dysregulation: consequences on parvalbumin interneurons, and their perineuronal nets. Neurobiol Dis 109:64–75

    Article  CAS  PubMed  Google Scholar 

  118. Nakazawa K, Sapkota K (2020) The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther 205:107426

    Article  CAS  PubMed  Google Scholar 

  119. Gysin R, Kraftsik R, Sandell J, Bovet P, Chappuis C, Conus P, Deppen P, Preisig M et al (2007) Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci 104(42):16621–16626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Baxter PS, Bell KF, Hasel P, Kaindl AM, Fricker M, Thomson D, Cregan SP, Gillingwater TH et al (2015) Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system. Nat Commun 6(1):1–13

    Article  Google Scholar 

  121. Mubarak B, Soriano FX, Hardingham GE (2009) Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene. Channels 3(4):233–239

    Article  Google Scholar 

  122. Mumtaz F, Khan MI, Zubair M, Dehpour AR (2018) Neurobiology and consequences of social isolation stress in animal model—a comprehensive review. Biomed Pharmacother 105:1205–1222

    Article  CAS  PubMed  Google Scholar 

  123. Yao JK, Keshavan MS (2011) Antioxidants, redox signaling, and pathophysiology in schizophrenia: an integrative view. Antioxidants & redox signaling 5(7):2011–2035

  124. Sampaio LRL, Cysne Filho FMS, de Almeida JC, dos Santos DD, Patrocínio CFV, de Sousa CNS, Patrocínio MCA, Macêdo D et al (2018) Advantages of the alpha-lipoic acid association with chlorpromazine in a model of schizophrenia induced by ketamine in rats: behavioral and oxidative stress evidences. Neuroscience 373:72–81

    Article  CAS  PubMed  Google Scholar 

  125. Zuo D-Y, Wu Y-L, Yao W-X, Cao Y, Wu C-F, Tanaka M (2007) Effect of MK-801 and ketamine on hydroxyl radical generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by in vivo microdialysis. Pharmacol Biochem Behav 86(1):1–7

    Article  CAS  PubMed  Google Scholar 

  126. Wesseling H, Want EJ, Guest PC, Rahmoune H, Holmes E, Bahn S (2015) Hippocampal proteomic and metabonomic abnormalities in neurotransmission, oxidative stress, and apoptotic pathways in a chronic phencyclidine rat model. J Proteome Res 14(8):3174–3187

    Article  CAS  PubMed  Google Scholar 

  127. Genius J, Geiger J, Dölzer A-L, Benninghoff J, Giegling I, Hartmann AM, Möller H-J, Rujescu D (2013) Glutamatergic dysbalance and oxidative stress in in vivo and in vitro models of psychosis based on chronic NMDA receptor antagonism. PloS one 8(7):e59395

  128. Gunduz-Bruce H (2009) The acute effects of NMDA antagonism: from the rodent to the human brain. Brain Res Rev 60(2):279–286

    Article  CAS  PubMed  Google Scholar 

  129. Frodl T, Amico F (2014) Is there an association between peripheral immune markers and structural/functional neuroimaging findings? Prog Neuropsychopharmacol Biol Psychiatry 48:295–303

    Article  CAS  PubMed  Google Scholar 

  130. Kayser MS, Dalmau J (2016) Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Focus 14(4):510–515

    Article  PubMed  PubMed Central  Google Scholar 

  131. Nerurkar A, Bitton A, Davis RB, Phillips RS, Yeh G (2013) When physicians counsel about stress: results of a national study. JAMA Intern Med 173(1):76–77

    Article  PubMed  PubMed Central  Google Scholar 

  132. Steullet P, Cabungcal J, Monin A, Dwir D, O’donnell P, Cuenod M, Do K (2016) Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: a “central hub” in schizophrenia pathophysiology? Schizophr Res 176(1):41–51

    Article  CAS  PubMed  Google Scholar 

  133. Bhandari R, Kaur J, Kaur S, Kuhad A (2021) The Nrf2 pathway in psychiatric disorders: pathophysiological role and potential targeting. Expert Opin Ther Targets 25(2):115–139

    Article  CAS  PubMed  Google Scholar 

  134. Zhang J-c, Yao W, Dong C, Han M, Shirayama Y, Hashimoto K (2018) Keap1–Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. Eur Arch Psychiatry Clin Neurosci 268(8):865–870

    Article  PubMed  Google Scholar 

  135. Behrens MM, Ali SS, Dugan LL (2008) Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci 28(51):13957–13966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sorce S, Schiavone S, Tucci P, Colaianna M, Jaquet V, Cuomo V, Dubois-Dauphin M, Trabace L et al (2010) The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses. J Neurosci 30(34):11317–11325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Barron H, Hafizi S, Andreazza AC, Mizrahi R (2017) Neuroinflammation and oxidative stress in psychosis and psychosis risk. Int J Mol Sci 18(3):651

    Article  PubMed Central  Google Scholar 

  138. Hou Y, Zhang H, Xie G, Cao X, Zhao Y, Liu Y, Mao Z, Yang J et al (2013) Neuronal injury, but not microglia activation, is associated with ketamine-induced experimental schizophrenic model in mice. Prog Neuropsychopharmacol Biol Psychiatry 45:107–116

    Article  CAS  PubMed  Google Scholar 

  139. Zhou Y, Zheng W, Liu W, Wang C, Zhan Y, Li H, Chen L, Li M et al (2018) Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression. Brain Behav Immun 74:205–212

    Article  CAS  PubMed  Google Scholar 

  140. Reus GZ, Becker IR, Scaini G, Petronilho F, Oses JP, Kaddurah-Daouk R, Ceretta LB, Zugno AI et al (2018) The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 81:55–63

    Article  CAS  PubMed  Google Scholar 

  141. Das TK, Javadzadeh A, Dey A, Sabesan P, Théberge J, Radua J, Palaniyappan L (2019) Antioxidant defense in schizophrenia and bipolar disorder: a meta-analysis of MRS studies of anterior cingulate glutathione. Prog Neuropsychopharmacol Biol Psychiatry 91:94–102

    Article  CAS  PubMed  Google Scholar 

  142. Demro C, Rowland L, Wijtenburg SA, Waltz J, Gold J, Kline E, Thompson E, Reeves G et al (2017) Glutamatergic metabolites among adolescents at risk for psychosis. Psychiatry Res 257:179–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Matsuzawa D, Obata T, Shirayama Y, Nonaka H, Kanazawa Y, Yoshitome E, Takanashi J, Matsuda T, Shimizu E, Ikehira H (2008) Negative correlation between brain glutathione level and negative symptoms in schizophrenia: a 3T 1H-MRS study. PloS one 3(4):e1944

  144. Tsai M-C, Liou C-W, Lin T-K, Lin I-M, Huang T-L (2013) Changes in oxidative stress markers in patients with schizophrenia: the effect of antipsychotic drugs. Psychiatry Res 209(3):284–290

    Article  CAS  PubMed  Google Scholar 

  145. Şimşek Ş, Gençoğlan S, Yüksel T, Kaplan İ, Alaca R, Aktaş H (2016) Oxidative stress and DNA damage in untreated first-episode psychosis in adolescents. Neuropsychobiology 73(2):92–97

    Article  PubMed  Google Scholar 

  146. Miljevic C, Nikolic M, Nikolic-Kokic A, Jones DR, Niketic V, Lecic-Tosevski D, Spasic MB (2010) Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 34(2):303–307

    Article  CAS  PubMed  Google Scholar 

  147. Steullet P, Lavoie S, Kraftsik R, Guidi R, Gysin R, Cuénod M, Do KQ (2008) A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons. Free Radical Biol Med 44(6):1042–1054

    Article  CAS  Google Scholar 

  148. Stojković T, Radonjić NV, Velimirović M, Jevtić G, Popović V, Doknić M, Petronijević ND (2012) Risperidone reverses phencyclidine induced decrease in glutathione levels and alterations of antioxidant defense in rat brain. Prog Neuropsychopharmacol Biol Psychiatry 39(1):192–199

    Article  PubMed  Google Scholar 

  149. Breier A, Liffick E, Hummer TA, Vohs JL, Yang Z, Mehdiyoun NF, Visco AC, Metzler E et al (2018) Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders. Schizophr Res 199:395–402

    Article  PubMed  Google Scholar 

  150. Bulut M, Savas HA, Altindag A, Virit O, Dalkilic A (2009) Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia. The World Journal of Biological Psychiatry 10(4–2):626–628

    Article  PubMed  Google Scholar 

  151. Klauser P, Xin L, Fournier M, Griffa A, Cleusix M, Jenni R, Cuenod M, Gruetter R et al (2018) N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial. Transl Psychiatry 8(1):1–8

    Article  CAS  Google Scholar 

  152. Cabungcal J-H, Steullet P, Kraftsik R, Cuenod M, Do KQ (2013) Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiat 73(6):574–582

    Article  CAS  PubMed  Google Scholar 

  153. Phensy A, Duzdabanian HE, Brewer S, Panjabi A, Driskill C, Berz A, Peng G, Kroener S (2017) Antioxidant treatment with N-acetyl cysteine prevents the development of cognitive and social behavioral deficits that result from perinatal ketamine treatment. Front Behav Neurosci 11:106

    Article  PubMed  PubMed Central  Google Scholar 

  154. Bošković M, Vovk T, Koprivšek J, Plesničar BK, Grabnar I (2016) Vitamin E and essential polyunsaturated fatty acids supplementation in schizophrenia patients treated with haloperidol. Nutr Neurosci 19(4):156–161

    Article  PubMed  Google Scholar 

  155. Faizi M, Salimi A, Rasoulzadeh M, Naserzadeh P, Pourahmad J (2014) Schizophrenia induces oxidative stress and cytochrome C release in isolated rat brain mitochondria: a possible pathway for induction of apoptosis and neurodegeneration. Iran J Pharm Res 13(Suppl):93

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Özyurt H, Özyurt B, Sarsılmaz M, Kuş İ, Songür A, Akyol Ö (2014) Potential role of some oxidant/antioxidant status parameters in prefrontal cortex of rat brain in an experimental psychosis model and the protective effects of melatonin 18(15):2137–2144

  157. Pertierra LR, Hughes KA, Vega GC, Olalla-Tárraga MÁ (2017) High resolution spatial mapping of human footprint across Antarctica and its implications for the strategic conservation of avifauna. PloS One 12(1):e0168280

    Article  PubMed  PubMed Central  Google Scholar 

  158. Vickers NJ (2017) Animal communication: when i’m calling you, will you answer too? Curr Biol 27(14):R713–R715

    Article  CAS  PubMed  Google Scholar 

  159. Kulak A, Cuenod M, Do KQ (2012) Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behav Brain Res 226(2):563–570

    Article  CAS  PubMed  Google Scholar 

  160. Steullet P, Cabungcal J, Bukhari S, Ardelt M, Pantazopoulos H, Hamati F, Salt T, Cué nod M et al (2018) The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbuminexpressing neuron networks and oxidative stress. Mol Psychiatry 23:2057–2065

    Article  CAS  PubMed  Google Scholar 

  161. Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, Quinlan EM, Nakazawa K (2010) Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 13(1):76

    Article  CAS  PubMed  Google Scholar 

  162. Jadi MP, Behrens MM, Sejnowski TJ (2016) Abnormal gamma oscillations in N-methyl-D-aspartate receptor hypofunction models of schizophrenia. Biol Psychiat 79(9):716–726

    Article  CAS  PubMed  Google Scholar 

  163. Tatard-Leitman VM, Jutzeler CR, Suh J, Saunders JA, Billingslea EN, Morita S, White R, Featherstone RE et al (2015) Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability. Biol Psychiat 77(6):556–568

    Article  CAS  PubMed  Google Scholar 

  164. Huria T, Beeraka NM, Al-Ghamdi B, Fern R (2015) Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury. J Cereb Blood Flow Metab 35(4):543–553

    Article  CAS  PubMed  Google Scholar 

  165. Huria T, Beeraka N, Elgradawi M, Elzwei S (2005) Picrotoxin (GABAA receptor antagonist) shows a protective role in brain injury during neonatal development

  166. Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35(1):57–67

    Article  CAS  PubMed  Google Scholar 

  167. Anderson KM, Collins MA, Chin R, Ge T, Rosenberg MD, Holmes AJ (2020) Transcriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk. Nat Commun 11(1):1–15

    Article  Google Scholar 

  168. Behrens MM, Sejnowski TJ (2009) Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology 57(3):193–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Jiang Z, Cowell RM, Nakazawa K (2013) Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia. Front Behav Neurosci 7:116

    Article  PubMed  PubMed Central  Google Scholar 

  170. Steullet P, Cabungcal J, Coyle J, Didriksen M, Gill K, Grace A, Hensch T, LaMantia A et al (2017) Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry 22(7):936–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Powell SB, Sejnowski TJ, Behrens MM (2012) Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia. Neuropharmacology 62(3):1322–1331

    Article  CAS  PubMed  Google Scholar 

  172. Yolland CO, Hanratty D, Neill E, Rossell SL, Berk M, Dean OM, Castle DJ, Tan EJ et al (2020) Meta-analysis of randomised controlled trials with N-acetylcysteine in the treatment of schizophrenia. Aust N Z J Psychiatry 54(5):453–466

    Article  PubMed  Google Scholar 

  173. Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F et al (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiat 64(5):361–368

    Article  CAS  PubMed  Google Scholar 

  174. Farokhnia M, Azarkolah A, Adinehfar F, Khodaie-Ardakani M-R, Yekehtaz H, Tabrizi M, Rezaei F, Salehi B et al (2013) N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol 36(6):185–192

    Article  CAS  PubMed  Google Scholar 

  175. Lavoie S, Murray MM, Deppen P, Knyazeva MG, Berk M, Boulat O, Bovet P, Bush AI et al (2008) Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients. Neuropsychopharmacology 33(9):2187–2199

    Article  CAS  PubMed  Google Scholar 

  176. Zheng W, Zhang QE, Cai DB, Yang XH, Qiu Y, Ungvari G, Ng C, Berk M et al (2018) N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials. Acta Psychiatr Scand 137(5):391–400

    Article  CAS  PubMed  Google Scholar 

  177. Rapado-Castro M, Dodd S, Bush A, Malhi G, Skvarc D, On Z, Berk M, Dean O (2017) Cognitive effects of adjunctive N-acetyl cysteine in psychosis. Psychol Med 47(5):866–876

    Article  CAS  PubMed  Google Scholar 

  178. Sepehrmanesh Z, Heidary M, Akasheh N, Akbari H, Heidary M (2018) Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: a double-blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry 82:289–296

    Article  CAS  PubMed  Google Scholar 

  179. Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, Ferrari C, Cousins A et al (2018) N-acetylcysteine in a double-blind randomized placebo-controlled trial: toward biomarker-guided treatment in early psychosis. Schizophr Bull 44(2):317–327

    Article  PubMed  Google Scholar 

  180. McQueen G, Lay A, Lally J, Gabay AS, Collier T, Lythgoe DJ, Barker GJ, Stone JM et al (2020) Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia. Psychopharmacology 237(2):443–451

    Article  CAS  PubMed  Google Scholar 

  181. Singh V, Singh SP, Chan K (2010) Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharm 13(2):257–271

    Article  CAS  Google Scholar 

  182. Doruk A, Uzun Ö, Özsahin A (2008) A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 23(4):223–227

    Article  PubMed  Google Scholar 

  183. Zhang W-F, Tan Y-L, Zhang X-Y, Chan RC, Wu H-R, Zhou D-F (2010) Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 71 (5):0–0

  184. Rathbone J, Zhang L, Zhang M, Xia J, Liu X, Yang Y (2005) Chinese herbal medicine for schizophrenia. Cochrane Database of Systematic Reviews 4(190):379–384

  185. Amiri A, Noorbala AA, Nejatisafa AA, Ghoreishi A, Derakhshan MK, Khodaie-Ardakani MR, Hajiazim M, Raznahan M et al (2008) Efficacy of selegiline add on therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study. Hum Psychopharmacol Clin Exp 23(2):79–86

    Article  CAS  Google Scholar 

  186. Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR, Smirnova LP (2021) Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives. Oxidative Medicine and Cellular Longevity 8881770 

  187. Bodkin JA, Siris SG, Bermanzohn PC, Hennen J, Cole JO (2005) Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia. Am J Psychiatry 162(2):388–390

    Article  PubMed  Google Scholar 

  188. Akhondzadeh S, Safarcherati A, Amini H (2005) Beneficial antipsychotic effects of allopurinol as add-on therapy for schizophrenia: a double blind, randomized and placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 29(2):253–259

    Article  CAS  PubMed  Google Scholar 

  189. Brunstein MG, Ghisolfi ES, Ramos FL, Lara DR (2005) A clinical trial of adjuvant allopurinol therapy for moderately refractory schizophrenia. J Clin Psychiatry 66(2):213–219

    Article  CAS  PubMed  Google Scholar 

  190. Dickerson FB, Stallings CR, Origoni AE, Sullens A, Khushalani S, Sandson N, Yolken RH (2009) A double-blind trial of adjunctive allopurinol for schizophrenia. Schizophr Res 109(1–3):66–69

    Article  PubMed  Google Scholar 

  191. Weiser M, Gershon AA, Rubinstein K, Petcu C, Ladea M, Sima D, Podea D, Keefe RS et al (2012) A randomized controlled trial of allopurinol vs. placebo added on to antipsychotics in patients with schizophrenia or schizoaffective disorder. Schizophr Res 138(1):35–38

    Article  PubMed  Google Scholar 

  192. Adler LA (1993) Vitamin E in tardive dyskinesia: time course of effect after. Psychopharmacol Bull 29(3):371

    CAS  PubMed  Google Scholar 

  193. Adler LA, Edson R, Lavori P, Peselow E, Duncan E, Rosenthal M, Rotrosen J (1998) Long-term treatment effects of vitamin E for tardive dyskinesia. Biol Psychiat 43(12):868–872

    Article  CAS  PubMed  Google Scholar 

  194. Lohr JB, Caligiuri MP (1996) A double-blind placebo-controlled study of vitamin E treatment of tardive dyskinesia. J Clin Psychiatry 57(4):167–173

    CAS  PubMed  Google Scholar 

  195. Zhang XY, Zhou DF, Cao LY, Xu CQ, Wu GY (2004) The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind placebo-controlled trial. J Clin Psychopharmacol 24(1):83–86

    Article  PubMed  Google Scholar 

  196. Sajjad SHA (1998) Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 months at different doses. International Clinical Psychopharmacology 13(4):147–55

  197. Soares‐Weiser K, Maayan N, Bergman H (2018) Vitamin E for antipsychotic‐induced tardive dyskinesia. Cochrane Database of Systematic Reviews 1(1):CD000209

  198. Dakhale G, Khanzode S, Khanzode S, Saoji A (2005) Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacology 182(4):494–498

    Article  CAS  PubMed  Google Scholar 

  199. Michael N, Sourgens H, Arolt V, Erfurth A (2002) Severe tardive dyskinesia in affective disorders: treatment with vitamin E and C. Neuropsychobiology 46(Suppl. 1):28–30

    Article  CAS  PubMed  Google Scholar 

  200. Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP (2003) Supplementation with a combination of ω-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res 62(3):195–204

    Article  PubMed  Google Scholar 

  201. Sivrioglu E, Kirli S, Sipahioglu D, Gursoy B, Sarandöl E (2007) The impact of ω-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: An open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 31(7):1493–1499

    Article  CAS  PubMed  Google Scholar 

  202. Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ (2002) Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 159(9):1596–1598

    Article  PubMed  Google Scholar 

  203. Emsley R, Niehaus DJ, Koen L, Oosthuizen PP, Turner HJ, Carey P, van Rensburg SJ, Maritz JS et al (2006) The effects of eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo-controlled trial. Schizophr Res 84(1):112–120

    Article  PubMed  Google Scholar 

  204. Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M (2001) A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 158(12):2071–2074

    Article  CAS  PubMed  Google Scholar 

  205. Peet M, Brind J, Ramchand C, Shah S, Vankar G (2001) Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 49(3):243–251

    Article  CAS  PubMed  Google Scholar 

  206. Pawełczyk T, Grancow M, Kotlicka-Antczak M, Trafalska E, Gębski P, Szemraj J, Żurner N, Pawełczyk A (2015) Omega-3 fatty acids in first-episode schizophrenia-a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods. BMC Psychiatry 15(1):1–13

    Article  Google Scholar 

  207. Sedlak TW, Nucifora LG, Koga M, Shaffer LS, Higgs C, Tanaka T, Wang AM, Coughlin JM et al (2017) Sulforaphane augments glutathione and influences brain metabolites in human subjects: a clinical pilot study. Mol Neuropsychiatry 3(4):214–222

    CAS  Google Scholar 

  208. Shiina A, Kanahara N, Sasaki T, Oda Y, Hashimoto T, Hasegawa T, Yoshida T, Iyo M et al (2015) An open study of sulforaphane-rich broccoli sprout extract in patients with schizophrenia. Clin Psychopharm Neurosci 13(1):62

    Article  CAS  Google Scholar 

  209. Shirai Y, Fujita Y, Hashimoto R, Ohi K, Yamamori H, Yasuda Y, Ishima T, Suganuma H et al (2015) Dietary intake of sulforaphane-rich broccoli sprout extracts during juvenile and adolescence can prevent phencyclidine-induced cognitive deficits at adulthood. PLoS One 10(6):e0127244

    Article  PubMed  PubMed Central  Google Scholar 

  210. Xu L-L, Wu Y-F, Yan F, Li C-C, Dai Z, You Q-D, Jiang Z-Y, Di B (2019) 5-(3, 4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1, 2, 4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson’s disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress. Free Radical Biol Med 134:288–303

    Article  CAS  Google Scholar 

  211. Miodownik C, Lerner V, Kudkaeva N, Lerner PP, Pashinian A, Bersudsky Y, Eliyahu R, Kreinin A et al (2019) Curcumin as add-on to antipsychotic treatment in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. Clin Neuropharmacol 42(4):117–122

    Article  PubMed  Google Scholar 

  212. Zortea K, Franco VC, Francesconi LP, Cereser KM, Lobato MIR, Belmonte-de-Abreu PS (2016) Resveratrol supplementation in schizophrenia patients: a randomized clinical trial evaluating serum glucose and cardiovascular risk factors. Nutrients 8(2):73

    Article  PubMed  PubMed Central  Google Scholar 

  213. Cao Y, Yan Z, Zhou T, Wang G (2017) SIRT1 regulates cognitive performance and ability of learning and memory in diabetic and nondiabetic models. Journal of Diabetes Research 7121827

  214. Magaji MG, Iniaghe LO, Abolarin M, Abdullahi OI, Magaji RA (2017) Neurobehavioural evaluation of resveratrol in murine models of anxiety and schizophrenia. Metab Brain Dis 32(2):437–442

    Article  CAS  PubMed  Google Scholar 

  215. Huang Q, Ye X, Wang L, Pan J (2019) Salvianolic acid B abolished chronic mild stress-induced depression through suppressing oxidative stress and neuro-inflammation via regulating NLRP3 inflammasome activation. J Food Biochem 43(3):e12742

    PubMed  Google Scholar 

  216. Yu L, An C, Jia L, Li Y, Chen Q, Zhen F, Wang S, Wang M (2016) Combination therapy of salvianolic acid and fluoxetine improves the cognitive function of rats with chronic stress-induced depression. World Neurosurg 86:173–180

    Article  PubMed  Google Scholar 

  217. Liao D, Chen Y, Guo Y, Wang C, Liu N, Gong Q, Fu Y, Fu Y et al (2020) Salvianolic acid B improves chronic mild stress-induced depressive behaviors in rats: involvement of AMPK/SIRT1 signaling pathway. J Inflamm Res 13:195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Jiang W-L, Cai D-B, Yin F, Zhang L, Zhao X-W, He J, Ng CH, Ungvari GS et al (2020) Adjunctive metformin for antipsychotic-induced dyslipidemia: a meta-analysis of randomized, double-blind, placebo-controlled trials. Transl Psychiatry 10(1):1–9

    Article  CAS  Google Scholar 

  219. Pérez-Torres I, Guarner-Lans V, Rubio-Ruiz ME (2017) Reductive stress in inflammation-associated diseases and the pro-oxidant effect of antioxidant agents. Int J Mol Sci 18(10):2098

    Article  PubMed Central  Google Scholar 

  220. Large CH (2007) Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol 21(3):283–301

    Article  CAS  PubMed  Google Scholar 

  221. Kriisa K, Haring L, Vasar E, Koido K, Janno S, Vasar V, Zilmer K, Zilmer M (2016) Antipsychotic treatment reduces indices of oxidative stress in first-episode psychosis patients. Oxidative medicine and cellular longevity 9616593

  222. Flatow J, Buckley P, Miller BJ (2013) Meta-analysis of oxidative stress in schizophrenia. Biol Psychiat 74(6):400–409

    Article  CAS  PubMed  Google Scholar 

  223. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, Arndt T, Bäckers L et al (2019) Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 394(10202):939–951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Chikowe I, Domingo M, Mwakaswaya V, Parveen S, Mafuta C, Kampira E (2019) Adverse drug reactions experienced by out-patients taking chlorpromazine or haloperidol at Zomba Mental Hospital. Malawi BMC Research notes 12(1):1–6

    CAS  Google Scholar 

  225. Boyda HN, Ho AA, Tse L, Procyshyn RM, Yuen JW, Kim DD, Honer WG, Barr AM (2020) Differential effects of acute treatment with antipsychotic drugs on peripheral catecholamines. Frontiers in Psychiatry 11:617428

  226. Boll KM, Noto C, Bonifácio KL, Bortolasci CC, Gadelha A, Bressan RA, Barbosa DS, Maes M et al (2017) Oxidative and nitrosative stress biomarkers in chronic schizophrenia. Psychiatry Res 253:43–48

    Article  CAS  PubMed  Google Scholar 

  227. Zhang XY, Zhou DF, Qi LY, Chen S, Cao LY, Xiu MH, Wang F, Wu GY et al (2009) Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics. Psychopharmacology 204(1):177–184

    Article  CAS  PubMed  Google Scholar 

  228. Bai Z-L, Li X-S, Chen G-Y, Du Y, Wei Z-X, Chen X, Zheng G-E, Deng W et al (2018) Serum oxidative stress marker levels in unmedicated and medicated patients with schizophrenia. J Mol Neurosci 66(3):428–436

    Article  CAS  PubMed  Google Scholar 

  229. Zhang XY, Zhou DF, Shen YC, Zhang PY, Zhang WF, Liang J, Xiu MH, Kosten TA et al (2012) Effects of risperidone and haloperidol on superoxide dismutase and nitric oxide in schizophrenia. Neuropharmacology 62(5–6):1928–1934

    Article  CAS  PubMed  Google Scholar 

  230. Kulaksizoglu B, Kulaksizoglu S (2018) Thiol/disulfide homeostasis in schizophrenic patients. Neurochem J 12(1):102–106

    Article  CAS  Google Scholar 

  231. Topcuoglu C, Bakirhan A, Yilmaz FM, Neselioglu S, Erel O, Sahiner SY (2017) Thiol/disulfide homeostasis in untreated schizophrenia patients. Psychiatry Res 251:212–216

    Article  CAS  PubMed  Google Scholar 

  232. Ünal K, Erzin G, Yüksel RN, Alisik M, Erel Ö (2018) Thiol/disulphide homeostasis in schizophrenia patients with positive symptoms. Nord J Psychiatry 72(4):281–284

    Article  PubMed  Google Scholar 

  233. An H, Du X, Huang X, Qi L, Jia Q, Yin G, Xiao C, Huang X-F et al (2018) Obesity, altered oxidative stress, and clinical correlates in chronic schizophrenia patients. Transl Psychiatry 8(1):1–7

    Article  Google Scholar 

  234. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, Krogh J, Benros ME (2019) Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry 24(6):869–887

    Article  CAS  PubMed  Google Scholar 

  235. González-Blanco L, García-Portilla MP, García-Álvarez L, de la Fuente-Tomás L, García CI, Sáiz PA, Rodríguez-González S, Coto-Montes A et al (2018) Oxidative stress biomarkers and clinical dimensions in first 10 years of schizophrenia. Rev Psiquiatr Salud Ment (Engl Ed) 11(3):130–140

    Article  Google Scholar 

  236. Smaga I, Niedzielska E, Gawlik M, Moniczewski A, Krzek J, Pera J, Filip M, Przegalin E (2015) Pharmacological reports oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2 Depression, anxiety, schizophrenia and autism. Pharmacol Rep 67:569–580

    Article  CAS  PubMed  Google Scholar 

  237. Ng F, Berk M, Dean O, Bush AI (2008) Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol 11(6):851–876

    Article  CAS  PubMed  Google Scholar 

  238. Nikitina IL, Beeraka NM, Gaisina GG, Bulygin KV, Galimova EF, Galimov SN, Nikolenko VN, Mikhaleva LM, Somasundaram SG, Kirkland CE (2020) In vivo antidepressant efficacy of 3-substituted Thietane-1, 1-dioxide derivative—a preliminary study for novel anti-depression therapy in neurological disorders

  239. Beeraka NM, Doreswamy SH, Sadhu SP, Srinivasan A, Pragada RR, Madhunapantula SV, Aliev G (2020) The role of exosomes in stemness and neurodegenerative diseases—chemoresistant-cancer therapeutics and phytochemicals. Int J Mol Sci 21(18):6818

    Article  CAS  PubMed Central  Google Scholar 

  240. Cunha AS, Matheus FC, Moretti M, Sampaio TB, Poli A, Santos DB, Colle D, Cunha MP, Blum-Silva CH, Sandjo LP (2016) Agmatine attenuates reserpine-induced oral dyskinesia in mice: role of oxidative stress, nitric oxide and glutamate NMDA receptors. Behav Brain Res 312:64–76

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by GALLY International Research Institute, San Antonio, Texas, USA, and by the Russian Academic Excellence project "5–100″ for the Sechenov University, Moscow, Russia.

Author information

Authors and Affiliations

  1. Department of Human Anatomy, I M Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia

    Narasimha M. Beeraka & Gjumrakch Aliev

  2. Faculty of Health Sciences, Department of Clinical Sciences, Barrio Santa Helena, University of Tolima, 730006, Ibagué, Colombia

    Marco F. Avila-Rodriguez

  3. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region, 142432, Russia

    Gjumrakch Aliev

  4. Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russia

    Gjumrakch Aliev

  5. GALLY International Research Institute, 7733 Louis Pasteur Drive, #330, San Antonio, TX, 78229, USA

    Gjumrakch Aliev

Authors
  1. Narasimha M. Beeraka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco F. Avila-Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gjumrakch Aliev
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Narasimha M Beeraka (NMB), Marco F. Avila-Rodriguez (MAR), and Gjumrakch Aliev (GA) conceptualized, designed the study, collected, analyzed the data, and performed the formal analysis. All of authors’ discussed the analyses, the results and their interpretation, wrote the original manuscript, revised and improved the original draft. All authors have reviewed and approved the manuscript before submission.

Corresponding author

Correspondence to Narasimha M. Beeraka.

Ethics declarations

Ethics Approval

No animal or human used in this study. All of the data was collected from open scientific and public sources.

Consent to Participate

Not applicable.

Consent for Publication

None.

Conflict of Interest

The authors declare no 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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beeraka, N.M., Avila-Rodriguez, M.F. & Aliev, G. Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia. Mol Neurobiol 59, 2472–2496 (2022). https://doi.org/10.1007/s12035-021-02703-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02703-4

Keywords

Search

Navigation