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Schizophrenia, Curcumin and Minimizing Side Effects of Antipsychotic Drugs: Possible Mechanisms

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Abstract

Schizophrenia is a mental disorder characterized by episodes of psychosis; major symptoms include hallucinations, delusions, and disorganized thinking. More recent theories focus on particular disorders of interneurons, dysfunctions in the immune system, abnormalities in the formation of myelin, and augmented oxidative stress that lead to alterations in brain structure. Decreased dopaminergic activity and increased phospholipid metabolism in the prefrontal cortex might be involved in schizophrenia. Antipsychotic drugs used to treat schizophrenia have many side effects. Alternative therapy such as curcumin (CUR) can reduce the severity of symptoms without significant side effects. CUR has important therapeutic properties such as antioxidant, anti-mutagenic, anti-inflammatory, and antimicrobial functions and protection of the nervous system. Also, the ability of CUR to pass the blood–brain barrier raises new hopes for neuroprotection. CUR can improve and prevent further probable neurological and behavioral disorders in patients with schizophrenia. It decreases the side effects of neuroleptics and retains lipid homeostasis. CUR increases the level of brain-derived neurotrophic factor and improves hyperkinetic movement disorders. CUR may act as an added counteraction mechanism to retain cell integrity and defense against free radical injury. Thus it appears to have therapeutic potential for improvement of schizophrenia. In this study, we review several properties of CUR and its ability to improve schizophrenia and minimize the side effects of antipsychotic drugs, and we explore the underlying mechanisms by which CUR affects schizophrenia and its symptoms.

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Data Availability

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Abbreviations

CUR:

Curcumin

BDNF:

Brain-derived neurotrophic factor

CLO:

Clozapine

TD:

Tardive dyskinesia

EPSE:

Extrapyramidal side effects

AMPK:

AMP-activated protein kinase

ACC:

Acetyl CoA carboxylase

SREBPs:

Sterol regulatory element-binding proteins

CREB:

CAMP response element-binding protein

DISC1:

Disrupted-in-schizophrenia 1

NMDA:

N-methyl-d-aspartate

HDAC:

Histone deacetylase

PDB:

Protein data bank

References

  1. Schultz SH, North SW, Shields CG (2007) Schizophrenia: a review. Am Fam Physician 75:1821–1829

    PubMed  Google Scholar 

  2. Do K (2013) Schizophrenia: genes, environment and neurodevelopment. Revue Medicale Suisse 9(1672):1674–1677

    Google Scholar 

  3. Horga G, Bernacer J, Dusi N, Entis J, Chu K, Hazlett EA, Mehmet Haznedar M, Kemether E, Byne W, Buchsbaum MS (2011) Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia. Eur Arch Psychiatry Clin Neurosci 261:467–476

    Article  PubMed  PubMed Central  Google Scholar 

  4. Garey L, Ong W, Patel T, Kanani M, Davis A, Mortimer A, Barnes T, Hirsch S (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65:446–453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brunner J, Gattaz WF (1995) Intracerebroventricular injection of phospholipase A2 inhibits apomorphine-induced locomotion in rats. Psychiatry Res 58:165–169

    Article  CAS  PubMed  Google Scholar 

  6. Keshavan MS, Lawler AN, Nasrallah HA, Tandon R (2017) New drug developments in psychosis: challenges, opportunities and strategies. Prog Neurobiol 152:3–20

    Article  CAS  PubMed  Google Scholar 

  7. Miyamoto S, Jarskog LF, Fleischhacker WW (2014) New therapeutic approaches for treatment-resistant schizophrenia: a look to the future. J Psychiatr Res 58:1–6

    Article  PubMed  Google Scholar 

  8. Trebaticka J, Ďuračková Z (2015) Psychiatric disorders and polyphenols: can they be helpful in therapy? Oxidative Med Cell Longev 2015:1–16

    Article  Google Scholar 

  9. Goel A, Aggarwal BB (2010) Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer 62:919–930

    Article  CAS  PubMed  Google Scholar 

  10. Shehzad A, Rehman G, Lee YS (2013) Curcumin in inflammatory diseases. BioFactors 39:69–77

    Article  CAS  PubMed  Google Scholar 

  11. Anand P, Sung B, Kunnumakkara AB, Rajasekharan KN, Aggarwal BB (2011) RETRACTED: Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: role of Michael acceptors and Michael donors. Biochem Pharmacol. https://doi.org/10.1016/j.bcp.2011.09.001

    Article  PubMed  PubMed Central  Google Scholar 

  12. Polazzi E, Monti B (2010) Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog Neurobiol 92:293–315

    Article  PubMed  Google Scholar 

  13. Aggarwal BB, Kumar A, Bharti AC (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398

    CAS  PubMed  Google Scholar 

  14. Ullah F, Liang A, Rangel A, Gyengesi E, Niedermayer G, Münch G (2017) High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation. Arch Toxicol 91:1623–1634

    Article  CAS  PubMed  Google Scholar 

  15. Shireen E (2016) Experimental treatment of antipsychotic-induced movement disorders. J Exp Pharmacol 8:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhu LN, Mei X, Zhang ZG, Yp X, Lang F (2019) Curcumin intervention for cognitive function in different types of people: a systematic review and meta-analysis. Phytother Res 33:524–533

    Article  PubMed  Google Scholar 

  17. Insel TR (2010) Rethinking schizophrenia. Nature 468:187–193

    Article  CAS  PubMed  Google Scholar 

  18. Demirci K, Özçankaya R, Yilmaz HR, Yiğit A, Uğuz AC, Karakuş K, Demirdaş A, Akpınar A (2015) Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism. Redox Rep 20:170–176

    Article  CAS  PubMed  Google Scholar 

  19. Wang H, Liu S, Tian Y, Wu X, He Y, Li C, Namaka M, Kong J, Li H, Xiao L (2015) Quetiapine inhibits microglial activation by neutralizing abnormal STIM1-mediated intercellular calcium homeostasis and promotes myelin repair in a cuprizone-induced mouse model of demyelination. Front Cell Neurosci 9:492

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jimenez-Fernandez S, Gurpegui M, Diaz-Atienza F, Pérez-Costillas L, Gerstenberg M, Correll CU (2015) Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis. J Clin Psychiatry 76:1658–1667

    Article  PubMed  Google Scholar 

  21. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn (DSM-IV). American Psychiatric Organisation, Washington, DC

  22. Heinrichs RW, Zakzanis KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12:426

    Article  CAS  PubMed  Google Scholar 

  23. van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, Agartz I, Westlye LT, Haukvik UK, Dale AM (2016) Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry 21:547–553

    Article  PubMed  Google Scholar 

  24. Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? The American journal of psychiatry, Washington, D.C.

    Google Scholar 

  25. Jirsaraie RJ, Sheffield JM, Barch DM (2018) Neural correlates of global and specific cognitive deficits in schizophrenia. Schizophr Res 201:237–242

    Article  PubMed  PubMed Central  Google Scholar 

  26. Weinberger DR (1996) On the plausibility of “the neurodevelopmental hypothesis” of schizophrenia. Neuropsychopharmacology 14:1–11

    Article  Google Scholar 

  27. Upthegrove R (2009) Depression in schizophrenia and early psychosis: implications for assessment and treatment. Adv Psychiatr Treat 15:372–379

    Article  Google Scholar 

  28. Strassnig MT, Raykov T, O’Gorman C, Bowie CR, Sabbag S, Durand D, Patterson TL, Pinkham A, Penn DL, Harvey PD (2015) Determinants of different aspects of everyday outcome in schizophrenia: the roles of negative symptoms, cognition, and functional capacity. Schizophr Res 165:76–82

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lepage M, Bodnar M, Bowie CR (2014) Neurocognition: clinical and functional outcomes in schizophrenia. Can J Psychiatry 59:5–12

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ventura J, Hellemann GS, Thames AD, Koellner V, Nuechterlein KH (2009) Symptoms as mediators of the relationship between neurocognition and functional outcome in schizophrenia: a meta-analysis. Schizophr Res 113:189–199

    Article  PubMed  PubMed Central  Google Scholar 

  31. Walther S (2015) Psychomotor symptoms of schizophrenia map on the cerebral motor circuit. Psychiatry Res 233:293–298

    Article  PubMed  Google Scholar 

  32. Fischer BA, Buchanan RW (2017) Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham MA

  33. Chang W, Chan S, Chung D (2009) Diagnostic stability of functional psychosis: a systematic review. Hong Kong J Psychiatry 19:30

    Google Scholar 

  34. Robins E, Guze SB (1970) Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 126:983–987

    Article  CAS  PubMed  Google Scholar 

  35. Ponizovsky AM, Grinshpoon A, Pugachev I, Nahon D, Ritsner M, Abramowitz MZ (2006) Changes in stability of first-admission psychiatric diagnoses over 14 years, based on cross-sectional data at three time points. ISR J PSYCHIATRY RELAT SCI 43:34

    PubMed  Google Scholar 

  36. Kendell R (2005) La estabilidad de los diagnósticos psiquiatricos. Psiquiatría Biológica 12:240–243

    Google Scholar 

  37. Kendell R (1974) The stability of psychiatric diagnoses. Br J Psychiatry 124:352–356

    Article  CAS  PubMed  Google Scholar 

  38. Gold JM (2004) Cognitive deficits as treatment targets in schizophrenia. Schizophr Res 72:21–28

    Article  PubMed  Google Scholar 

  39. Friedman JI, Wallenstein S, Moshier E, Parrella M, White L, Bowler S, Gottlieb S, Harvey PD, McGinn TG, Flanagan L (2010) The effects of hypertension and body mass index on cognition in schizophrenia. Am J Psychiatry 167:1232–1239

    Article  PubMed  Google Scholar 

  40. Goughari AS, Mazhari S, Pourrahimi AM, Sadeghi MM, Nakhaee N (2015) Associations between components of metabolic syndrome and cognition in patients with schizophrenia. J Psychiatric Pract® 21:190–197

    Article  Google Scholar 

  41. Briles JJ, Rosenberg DR, Brooks BA, Roberts MW, Diwadkar VA (2012) Review of the safety of second-generation antipsychotics: are they really" atypically" safe for youth and adults? Prim Care Companion CNS Disord 14:27253

    Google Scholar 

  42. Haleem DJ, Shireen E, Haleem M (2004) Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidol-induced catalepsy. Prog Neuropsychopharmacol Biol Psychiatry 28:1323–1329

    Article  CAS  PubMed  Google Scholar 

  43. Haleem DJ, Samad N, Haleem MA (2007) Reversal of haloperidol-induced extrapyramidal symptoms by buspirone: a time-related study. Behav Pharmacol 18:147–153

    Article  CAS  PubMed  Google Scholar 

  44. Casey DE (2000) Tardive dyskinesia: pathophysiology and animal models. J Clin Psychiatry 61:5–9

    CAS  PubMed  Google Scholar 

  45. Li C-R, Chung Y-C, Park T-W, Yang J-C, Kim K-W, Lee K-H, Hwang I-K (2009) Clozapine-induced tardive dyskinesia in schizophrenic patients taking clozapine as a first-line antipsychotic drug. World J Biol Psychiatry 10:919–924

    Article  PubMed  Google Scholar 

  46. Esposito E (2006) Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets 7:177–185

    Article  CAS  PubMed  Google Scholar 

  47. Shireen E, Pervez S, Masroor M, Ali WB, Rais Q, Khalil S, Tariq A, Haleem DJ (2014) Reversal of haloperidol induced motor deficits in rats exposed to repeated immobilization stress. Pak J Pharm Sci 27:1459

    CAS  PubMed  Google Scholar 

  48. Bishnoi M, Chopra K, Kulkarni SK (2008) Protective effect of Curcumin, the active principle of turmeric (Curcuma longa) in haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes in rat brain. Pharmacol Biochem Behav 88:511–522

    Article  CAS  PubMed  Google Scholar 

  49. Butler R, Radhakrishnan R (2012) Dementia. Clin Evid 9:1001

    Google Scholar 

  50. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  CAS  PubMed  Google Scholar 

  51. Naidu P, Kulkarni S (2004) Quercetin, a bioflavonoid, reverses haloperidol-induced catalepsy. Methods Find Exp Clin Pharmacol 26:323–326

    Article  CAS  PubMed  Google Scholar 

  52. Dietrich-Muszalska A, Olas B, Kontek B, Rabe-Jabłońska J (2011) Beta-glucan from Saccharomyces cerevisiae reduces plasma lipid peroxidation induced by haloperidol. Int J Biol Macromol 49:113–116

    Article  CAS  PubMed  Google Scholar 

  53. Kristóf E, Doan-Xuan Q, Sárvári AK, Klusóczki Á, Fischer-Posovszky P, Wabitsch M, Bacso Z, Bai P, Balajthy Z, Fésüs L (2016) Clozapine modifies the differentiation program of human adipocytes inducing browning. Transl Psychiatry 6:e963–e963

    Article  PubMed  PubMed Central  Google Scholar 

  54. McNamara RK, Jandacek R, Rider T, Tso P, Cole-Strauss A, Lipton JW (2011) Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity. Schizophr Res 129:66–73

    Article  PubMed  PubMed Central  Google Scholar 

  55. Li H, Min Q, Ouyang C, Lee J, He C, Zou M-H, Xie Z (2014) AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta (BBA)-Mol Basis Dis 1842:1844–1854

    Article  CAS  Google Scholar 

  56. Bulaj G, Ahern M, Kuhn A, Judkins Z, Bowen R, Chen Y (2016) Incorporating natural products, pharmaceutical drugs, self-care and digital/mobile health technologies into molecular-behavioral combination therapies for chronic diseases. Curr Clin Pharmacol 11:128–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Woodbury-Farina M, Cernovsky Z, Chiu S (2012) Proof of concept of randomized controlled study of curcumin C-3 complex as adjunct treatment in schizophrenia: effects on negative and depressive symptoms. In: Presented at Natural Bioactives Conference, Ontario, Canada

  58. Wynn JK, Green MF, Hellemann G, Karunaratne K, Davis MC, Marder SR (2018) The effects of curcumin on brain-derived neurotrophic factor and cognition in schizophrenia: a randomized controlled study. Schizophr Res 195:572–573

    Article  PubMed  Google Scholar 

  59. Kucukgoncu S, Guloksuz S, Tek C (2019) Effects of curcumin on cognitive functioning and inflammatory state in schizophrenia: a double-blind, placebo-controlled pilot trial. J Clin Psychopharmacol 39(2):182–184

    Article  CAS  PubMed  Google Scholar 

  60. Chiu SS, Woodbury-Farina M, Terpstra K et al (2018) Translating curry extract to novel therapeutic approach in schizophrenia: the emerging role of epigenetics signaling. Planta Medica 5(S01):DM02

    Google Scholar 

  61. Miodownik C, Lerner V, Kudkaeva N 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 

  62. Hosseininasab M, Zarghami M, Mazhari S et al (2021) Nanocurcumin as an add-on to antipsychotic drugs for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 41(1):25–30

    Article  CAS  PubMed  Google Scholar 

  63. Jang J, Jung Y, Seo SJ, Kim SM, Shim YJ, Cho SH, Chung SI, Yoon Y (2017) Berberine activates AMPK to suppress proteolytic processing, nuclear translocation and target DNA binding of SREBP-1c in 3T3-L1 adipocytes. Mol Med Rep 15:4139–4147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu Z, Cui C, Xu P, Dang R, Cai H, Liao D, Yang M, Feng Q, Yan X, Jiang P (2017) Curcumin activates AMPK pathway and regulates lipid metabolism in rats following prolonged clozapine exposure. Front Neurosci 11:558

    Article  PubMed  PubMed Central  Google Scholar 

  65. Soetikno V, Sari FR, Sukumaran V, Lakshmanan AP, Harima M, Suzuki K, Kawachi H, Watanabe K (2013) Curcumin decreases renal triglyceride accumulation through AMPK–SREBP signaling pathway in streptozotocin-induced type 1 diabetic rats. J Nutr Biochem 24:796–802

    Article  CAS  PubMed  Google Scholar 

  66. Ding L, Li J, Song B, Xiao X, Zhang B, Qi M, Huang W, Yang L, Wang Z (2016) Curcumin rescues high fat diet-induced obesity and insulin sensitivity in mice through regulating SREBP pathway. Toxicol Appl Pharmacol 304:99–109

    Article  CAS  PubMed  Google Scholar 

  67. Kang Q, Chen A (2009) Curcumin inhibits srebp-2 expression in activated hepatic stellate cells in vitro by reducing the activity of specificity protein-1. Endocrinology 150:5384–5394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. He M, Zhang Q, Deng C, Wang H, Huang X-F (2014) Olanzapine-activated AMPK signaling in the dorsal vagal complex is attenuated by histamine H1 receptor agonist in female rats. Endocrinology 155:4895–4904

    Article  PubMed  Google Scholar 

  69. Shao W, Yu Z, Chiang Y, Yang Y, Chai T, Foltz W, Lu H, Fantus IG, Jin T (2012) Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS ONE 7:e28784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Maithilikarpagaselvi N, Sridhar MG, Swaminathan RP, Sripradha R, Badhe B (2016) Curcumin inhibits hyperlipidemia and hepatic fat accumulation in high-fructose-fed male Wistar rats. Pharm Biol 54:2857–2863

    Article  CAS  PubMed  Google Scholar 

  71. Lee YK, Lee WS, Hwang JT, Kwon DY, Surh YJ, Park OJ (2009) Curcumin exerts antidifferentiation effect through AMPKα-PPAR-γ in 3T3-L1 adipocytes and antiproliferatory effect through AMPKα-COX-2 in cancer cells. J Agric Food Chem 57:305–310

    Article  CAS  PubMed  Google Scholar 

  72. Lone J, Choi JH, Kim SW, Yun JW (2016) Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem 27:193–202

    Article  CAS  PubMed  Google Scholar 

  73. Tong W, Wang Q, Sun D, Suo J (2016) Curcumin suppresses colon cancer cell invasion via AMPK-induced inhibition of NF-κB, uPA activator and MMP9. Oncol Lett 12:4139–4146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cokorinos EC, Delmore J, Reyes AR, Albuquerque B, Kjøbsted R, Jørgensen NO, Tran J-L, Jatkar A, Cialdea K, Esquejo RM (2017) Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. Cell Metab 25(1147–1159):e1110

    Google Scholar 

  75. Fernandes B, Steiner J, Berk M, Molendijk M, Gonzalez-Pinto A, Turck C, Nardin P, Gonçalves C (2015) Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 20:1108–1119

    Article  CAS  PubMed  Google Scholar 

  76. Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, Pang Q (2014) Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res 271:116–121

    Article  CAS  PubMed  Google Scholar 

  77. Zhang L, Luo J, Zhang M, Yao W, Ma X, Yu SY (2014) Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats. Int J Neuropsychopharmacol 17:793–806

    Article  CAS  PubMed  Google Scholar 

  78. Dong S, Zeng Q, Mitchell ES, Xiu J, Duan Y, Li C, Tiwari JK, Hu Y, Cao X, Zhao Z (2012) Curcumin enhances neurogenesis and cognition in aged rats: implications for transcriptional interactions related to growth and synaptic plasticity. PLoS ONE 7:e31211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fanaei H, Khayat S, Kasaeian A, Javadimehr M (2016) Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. Neuropeptides 56:25–31

    Article  CAS  PubMed  Google Scholar 

  80. Motaghinejad M, Motevalian M, Fatima S, Hashemi H, Gholami M (2017) Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats. Biomed Pharmacother 87:721–740

    Article  CAS  PubMed  Google Scholar 

  81. Green MJ, Matheson S, Shepherd A, Weickert C, Carr V (2011) Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 16:960–972

    Article  CAS  PubMed  Google Scholar 

  82. Xu Y, Ku B, Tie L, Yao H, Jiang W, Ma X, Li X (2006) Curcumin reverses the effects of chronic stress on behavior, the HPA axis, BDNF expression and phosphorylation of CREB. Brain Res 1122:56–64

    Article  CAS  PubMed  Google Scholar 

  83. Ren X, Rizavi HS, Khan MA, Bhaumik R, Dwivedi Y, Pandey GN (2014) Alteration of cyclic-AMP response element binding protein in the postmortem brain of subjects with bipolar disorder and schizophrenia. J Affect Disord 152:326–333

    Article  PubMed  Google Scholar 

  84. Brunner J, Gattaz WF (1995) Intracerebral injection of phospholipase A 2 inhibits dopamine-mediated behavior in rats: possible implications for schizophrenia. Eur Arch Psychiatry Clin Neurosci 246:13–16

    Article  CAS  PubMed  Google Scholar 

  85. Eckert G, Schaeffer E, Schmitt A, Maras A, Gattaz W (2011) Increased brain membrane fluidity in schizophrenia. Pharmacopsychiatry 44:161–162

    Article  CAS  PubMed  Google Scholar 

  86. Smesny S, Milleit B, Nenadic I, Preul C, Kinder D, Lasch J, Willhardt I, Sauer H, Gaser C (2010) Phospholipase A2 activity is associated with structural brain changes in schizophrenia. Neuroimage 52:1314–1327

    Article  CAS  PubMed  Google Scholar 

  87. Sharma S, Ying Z, Gomez-Pinilla F (2010) A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma. Exp Neurol 226:191–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Titsworth WL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, Liu NK, Shao H, Cao QL, Xu XM (2009) Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 57:1521–1537

    Article  PubMed  PubMed Central  Google Scholar 

  89. Liu NK, Deng LX, Zhang YP, Lu QB, Wang XF, Hu JG, Oakes E, Bonventre JV, Shields CB, Xu XM (2014) Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury. Ann Neurol 75:644–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chen S-Y, Huang P-H, Cheng H-J (2011) Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. Proc Natl Acad Sci USA 108:5861–5866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kulkarni S, Dhir A (2010) Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 24:317–324

    Article  CAS  PubMed  Google Scholar 

  92. Maruta H (2014) Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res 28:656–672

    Article  PubMed  Google Scholar 

  93. DiMauro S, Davidzon G (2005) Mitochondrial DNA and disease. Ann Med 37:222–232

    Article  CAS  PubMed  Google Scholar 

  94. Flippo KH, Strack S (2017) An emerging role for mitochondrial dynamics in schizophrenia. Schizophr Res 187:26–32

    Article  PubMed  PubMed Central  Google Scholar 

  95. Ben-Shachar D (2017) Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target. Schizophr Res 187:3–10

    Article  PubMed  Google Scholar 

  96. Chen J, Rogers SC, Kavdia M (2013) Analysis of kinetics of dihydroethidium fluorescence with superoxide using xanthine oxidase and hypoxanthine assay. Ann Biomed Eng 41:327–337

    Article  CAS  PubMed  Google Scholar 

  97. Häfeli UO, Riffle JS, Harris-Shekhawat L, Carmichael-Baranauskas A, Mark F, Dailey JP, Bardenstein D (2009) Cell uptake and in vitro toxicity of magnetic nanoparticles suitable for drug delivery. Mol Pharm 6:1417–1428

    Article  PubMed  Google Scholar 

  98. Jeng HA, Swanson J (2006) Toxicity of metal oxide nanoparticles in mammalian cells. J Environ Sci Health Part A 41:2699–2711

    Article  CAS  Google Scholar 

  99. Stroh A, Zimmer C, Gutzeit C, Jakstadt M, Marschinke F, Jung T, Pilgrimm H, Grune T (2004) Iron oxide particles for molecular magnetic resonance imaging cause transient oxidative stress in rat macrophages. Free Radical Biol Med 36:976–984

    Article  CAS  Google Scholar 

  100. Sadeghiani N, Barbosa L, Silva L, Azevedo R, Morais P, Lacava Z (2005) Genotoxicity and inflammatory investigation in mice treated with magnetite nanoparticles surface coated with polyaspartic acid. J Magn Magn Mater 289:466–468

    Article  CAS  Google Scholar 

  101. Veranth JM, Kaser EG, Veranth MM, Koch M, Yost GS (2007) Cytokine responses of human lung cells (BEAS-2B) treated with micron-sized and nanoparticles of metal oxides compared to soil dusts. Part Fibre Toxicol 4:1–18

    Article  Google Scholar 

  102. Pongrac IM, Pavičić I, Milić M, Ahmed LB, Babič M, Horák D, Vrček IV, Gajović S (2016) Oxidative stress response in neural stem cells exposed to different superparamagnetic iron oxide nanoparticles. Int J Nanomed 11:1701

    CAS  Google Scholar 

  103. Ji M-H, Qiu L-L, Yang J-J, Zhang H, Sun X-R, Zhu S-H, Li W-Y, Yang J-J (2015) Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice. Neurotoxicology 46:155–164

    Article  CAS  PubMed  Google Scholar 

  104. Nafisi S, Adelzadeh M, Norouzi Z, Sarbolouki MN (2009) Curcumin binding to DNA and RNA. DNA Cell Biol 28:201–208

    Article  CAS  PubMed  Google Scholar 

  105. Zhu H-t, Bian C, Yuan J-c, Chu W-h, Xiang X, Chen F, Wang C-s, Feng H, Lin J-k (2014) Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflammation 11:1–17

    Article  CAS  Google Scholar 

  106. Tiwari V, Chopra K (2012) Attenuation of oxidative stress, neuroinflammation, and apoptosis by curcumin prevents cognitive deficits in rats postnatally exposed to ethanol. Psychopharmacology 224:519–535

    Article  CAS  PubMed  Google Scholar 

  107. Haleagrahara N, Siew CJ, Ponnusamy K (2013) Effect of quercetin and desferrioxamine on 6-hydroxydopamine (6-OHDA) induced neurotoxicity in striatum of rats. J Toxicol Sci 38:25–33

    Article  CAS  PubMed  Google Scholar 

  108. Waseem M, Parvez S (2016) Neuroprotective activities of curcumin and quercetin with potential relevance to mitochondrial dysfunction induced by oxaliplatin. Protoplasma 253:417–430

    Article  CAS  PubMed  Google Scholar 

  109. Kuo C-P, Lu C-H, Wen L-L, Cherng C-H, Wong C-S, Borel CO, Ju D-T, Chen C-M, Wu C-T (2011) Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. J Am Soc Anesthesiol 115:1229–1238

    Article  CAS  Google Scholar 

  110. Singh A, Kureel AK, Dutta P, Kumar S, Rai AK (2018) Curcumin loaded chitin-glucan quercetin conjugate: synthesis, characterization, antioxidant, in vitro release study, and anticancer activity. Int J Biol Macromol 110:234–244

    Article  CAS  PubMed  Google Scholar 

  111. Liu L, Zhang W, Wang L, Li Y, Tan B, Lu X, Deng Y, Zhang Y, Guo X, Mu J (2014) Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis. Neurochem Res 39:1322–1331

    Article  CAS  PubMed  Google Scholar 

  112. Johnson SM, Gulhati P, Arrieta I, Wang X, Uchida T, Gao T, Evers BM (2009) Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res 29:3185–3190

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Barzegar A, Moosavi-Movahedi AA (2011) Intracellular ROS protection efficiency and free radical-scavenging activity of curcumin. PloS one 6(10):e26012

    Google Scholar 

  114. Naserzadeh P, Hafez AA, Abdorahim M, Abdollahifar MA, Shabani R, Peirovi H, Simchi A, Ashtari K (2018) Curcumin loading potentiates the neuroprotective efficacy of Fe3O4 magnetic nanoparticles in cerebellum cells of schizophrenic rats. Biomed Pharmacother 108:1244–1252

    Article  CAS  PubMed  Google Scholar 

  115. Marini S, De Berardis D, Vellante F, Santacroce R, Orsolini L, Valchera A, Girinelli G, Carano A, Fornaro M, Gambi F (2016) Celecoxib adjunctive treatment to antipsychotics in schizophrenia: a review of randomized clinical add-on trials. Mediat Inflamm 2016:1

    Article  Google Scholar 

  116. Chiu SS, Woodbury-Farina M, Terpstra K, Badmaev V, Cernovsky Z, Bureau Y, Jirui J, Raheb H, Husni M, Copen J, Shad M, Srivastava A, Sanchez V, Williams M, Khazaeipool Z, Carriere A, Chehade C (2017) Targeting Epigenetics Signaling with Curcumin: A Transformative Drug Lead in Treatment of Schizophrenia? Journal of Clinical Epigenetics 3

  117. Kristiansen LV, Patel SA, Haroutunian V, Meador-Woodruff JH (2010) Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia. Synapse 64:495–502

    Article  CAS  PubMed  Google Scholar 

  118. Huang H-C, Chang P, Lu S-Y, Zheng B-W, Jiang Z-F (2015) Protection of curcumin against amyloid-β-induced cell damage and death involves the prevention from NMDA receptor-mediated intracellular Ca2+ elevation. J Recept Signal Transduct 35:450–457

    Article  CAS  Google Scholar 

  119. Badmaev V, Cernovsky Z, Bureau Y, Jirui J, Raheb H (2017) Targeting epigenetics signaling with curcumin: a transformative drug lead in treatment of schizophrenia? J Clin Epigenet 3:32

    Google Scholar 

  120. Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM (2015) Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry 2:452–464

    Article  PubMed  Google Scholar 

  121. Jiménez-Osorio AS, Monroy A, Alavez S (2016) Curcumin and insulin resistance—molecular targets and clinical evidences. BioFactors 42:561–580

    Article  PubMed  Google Scholar 

  122. Jayanarayanan S, Smijin S, Peeyush K, Anju T, Paulose C (2013) NMDA and AMPA receptor mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rat: ameliorating effects of curcumin. Chemico-Biological Interact 201:39–48

    Article  CAS  Google Scholar 

  123. Lieberman JA, Papadakis K, Csernansky J, Litman R, Volavka J, Jia XD, Gage A (2009) A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia. Neuropsychopharmacology 34:1322–1329

    Article  CAS  PubMed  Google Scholar 

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SJ had the idea for the article and supervised the paper, RR performed the literature search and data collection, SHH and AG drafted and critically revised the work. All authors read and approved the final manuscript.

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Rabiee, R., Hosseini Hooshiar, S., Ghaderi, A. et al. Schizophrenia, Curcumin and Minimizing Side Effects of Antipsychotic Drugs: Possible Mechanisms. Neurochem Res 48, 713–724 (2023). https://doi.org/10.1007/s11064-022-03798-4

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