神经甾体在精神分裂症发病与治疗中作用的研究进展

doi:10.12092/j.issn.1009-2501.2018.06.019

摘要/Abstract

摘要：

研究表明神经甾体代谢可能与精神分裂症的发病和治疗密切相关，本文将从神经甾体的生物合成、其在精神分裂症中的变化、作用机制及辅助治疗、性别差异等方面分别阐述，探讨相关神经甾体在精神分裂症发病与治疗中的潜在作用，旨在为神经甾体辅助治疗精神分裂症提供理论依据，为其治疗干预和监测提供创新性靶点。

关键词: 神经甾体, 生物合成, 作用机制, 辅助治疗, 精神分裂症, 性别差异

Abstract:

The latest researches have shown that the metabolism of neurosteroids is probably involved in the pathogenesis of schizophrenia and associated with relevant treatment. This review will focus on the relationship between neurosteroids and schizophrenia, mainly from these perspectives: biosynthesis of neurosteroids, alternation of neurosteroids, mechanism of action and its auxiliary role in schizophrenia, gender differences etc. so as to provide theoretical references for applying neurosteroids in adjuvant treatment of schizophrenia.

Key words: neurosteroids, biosynthesis, mechanism of action, adjuvant treatment, schizophrenia, gender differences

中图分类号:

R749.3

曹婷，李娜娜，蔡骅琳. 神经甾体在精神分裂症发病与治疗中作用的研究进展[J]. 中国临床药理学与治疗学, 2018, 23(6): 709-714.

CAO Ting, LI Nana, CAI Hualin. Progress in neurosteroids related to the pathogenesis and treatment of schizophrenia[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(6): 709-714.

参考文献

［1］Reddy DS. Neurosteroids: Endogenous role in the human brian and therapeutic potentials［M］//. Progress in Brain Research. Amsterdam: Elsevier Science & Technology, 2010,186(186):113-137.
［2］Groves NJ, McGrath JJ, Burne TH. Vitamin D as a neurosteroid affecting the developing and adult brain［J］. Annu Rev Nutr, 2014, 34:117-141.
［3］Plesnicar BK. Personalized treatment of schizophrenia in everyday clinical practice: reality or fiction［J］? Psychiatr Danub, 2015,27(3):314-318.
［4］Sagud M. Treatment-resistant schizophrenia: challenges and implications for clinical practice［J］. Psychiatr Danub, 2015,27(3):319-326.
［5］Guennoun R, Labombarda F, Deniselle MG, et al. Progesterone and allopregnanolone in the central nervous system: Response to injury and implication for neuroprotection［J］. J Steroid Biochem Mol Biol, 2015,146(SI):48-61.
［6］Zhang P, Xie M Q, Ding Y, et al. Allopregnanolone enhances the neurogenesis of midbrain dopaminergicneurons in APPswe/PSEN1 mice［J］. Neuroscience, 2015,290:214226.
［7］Colciago A, Magnaghi V. Neurosteroids involvement in the epigenetic control of memory formation and storage［J］. Neural Plast, 2016:5985021.
［8］Luchetti S, Huitinga I, Swaab DF. Neurosteroid and GABA_A receptor alterations in Alzheimer's disease, Parkinson's disease and multiple sclerosis ［J］. Neuroscience, 2011,191(SI):6-21.
［9］Reddy DS.Role of anticonvulsant and antiepileptogenic neurosteroids in the pathophysiology and treatment of epilepsy［J］.Front Endocrinol (Lausanne),2011,2:38.
［10］Koethe D, Bortolato M, Piomelli D, et al. Improvement of general symptoms in a chronic psychotic patient treated with finasteride: case report［J］. Pharmacopsychiatry, 2008,41(3):115-116.
［11］Frau R, Abbiati F, Bini V, et al. Targeting neurosteroid synthesis as a therapy for schizophreniarelated alterations induced by early psychosocial stress［J］. Schizophr Res, 2015,168(3):640-648.
［12］Selvaraj V, Stocco DM. The changing landscape in translocator protein (TSPO) function［J］. Trends Endocrinol Metab, 2015,26(7):341-348.
［13］Marx CE, Bradford DW, Hamer RM, et al. Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence［J］. Neuroscience, 2011,191:78-90.
［14］Marx CE, Stevens RD, Shampine LJ, et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics ［J］. Neuropsychopharmacology, 2006, 31(6):1249-1263.
［15］Ritsner MS.Pregnenolone, dehydroepiandrosterone,and schizophrenia: alterations and clinical trials［J］.CNS Neurosci Ther,2010,16(1):32-44.
［16］VuksanCusa B, Sagud M, Mihaljevic-Peles A, et al. Metabolic syndrome and cortisol/DHEAS ratio in patients with bipolar disorder and schizophrenia［J］. Psychiatria Danubina, 2014,26(2):187-189.
［17］Bicikova M, Hill M, Ripova D, et al. Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia［J］. J Steroid Biochem Mol Biol, 2013,133:77-83.
［18］陆丽, 施懿凌. 精神分裂症发病机制及治疗靶点的研究现状［J］. 医学综述, 2015,21(9):1586-1588.
［19］Chisari M, Eisenman LN, Covey DF, et al. The sticky issue of neurosteroids and GABA(A) receptors［J］. Trends Neurosci, 2010,33(7):299-306.
［20］Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease［J］. Neuron, 2012,73(1):23-34.
［21］R Andrew Moore, Philip J Wiffen, Sheena Derr, et al. Gabapentin for chronic neuropathic pain in adults［M］. Hoboken: John Wiley & Sons, Ltd, 2009,92(11):online.
［22］Walker MC, Kullmann DM. Tonic GABA_A Receptor-Mediated Signaling in Epilepsy［J］. Epilepsia, 2011, 51(s5):14.
［23］Korinek M, Kapras V, Vyklicky V, et al. Neurosteroid modulation of N-methyl-D-aspartate receptors: molecular mechanism and behavioral effects［J］. Steroids, 2011,76(13):1409-1418.
［24］Kussius CL, Kaur N, Popescu GK. Pregnanolone sulfate promotes desensitization of activated NMDA receptors［J］. J Neurosci, 2009,29(21):6819-6827.
［25］Marx CE, Keefe RS, Buchanan RW, et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia［J］. Neuropsychopharmacology, 2009,34(8):1885-1903.
［26］Rohe HJ, Ahmed IS, Twist KE, et al. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding［J］. Pharmacol Ther, 2009,121(1):14-19.
［27］Thomas P, Pang Y, Dong J. Enhancement of cell surface expression and receptor functions of membrane progestin receptor alpha (mPRalpha) by progesterone receptor membrane component 1(PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors［J］. Endocrinology, 2014, 155(3):1107-1119.
［28］Guennoun R, Labombarda F, Gonzalez DM, et al. Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection.［J］. J Steroid Biochem Mol Biol, 2015, 146:48-61.
［29］Intlekofer KA, Petersen SL. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain［J］. Neuroscience, 2011,172:55-65.
［30］Dong AM, JI XF, LU LL, et al. Effects of σ receptor agonists on learning and memory impairment in rats［D］. J Shenyang Pharmaceutical University, 2007.
［31］Li W, Jin X, Covey DF, et al. Neuroactive steroids and human recombinant rho1 GABAC receptors［J］. J Pharmacol Exp Ther, 2007,323(1):236-247.
［32］Tuem KB, Atey TM. Neuroactive ateroids: Receptor interactions and responses［J］. Front Neurol, 2017,8:442.
［33］蔡骅琳, 江沛, 李焕德, 等. 下丘脑垂体肾上腺轴与精神分裂症的关系［J］. 中国神经精神疾病杂志, 2013(11):688-691.
［34］Crowley SK, Girdler SS. Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans ［J］? Psychopharmacology (Berl), 2014,231(17):3619-3634.
［35］Cai H, Cao T, Zhou X, et al. Neurosteroids in schizophrenia: Pathogenic and therapeutic implications［J］. Front Psychiatry, 2018,9:73-80.
［36］Wong P, Sze Y, Chang CC, et al. Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3beta pathway［J］. Transl Psychiatry, 2015,5(3):e528.
［37］Marx CE, Lee J, Subramaniam M, et al. Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia［J］. Psychopharmacology (Berl), 2014,231(17):3647-3662.
［38］Marx CE, Shampine LJ, Duncan GE, et al. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy ［J］? Pharmacol Biochem Behav, 2006,84(4):598-608.
［39］Pouget JG, Goncalves VF, Nurmi EL, et al. Investigation of TSPO variants in schizophrenia and antipsychotic treatment outcomes［J］. Pharmacogenomics, 2015,16(1):5-22.
［40］Kardashev A, Ratner Y, Ritsner MS. Addon pregnenolone with L-theanine to antipsychotic therapy relieves negative and anxiety symptoms of schizophrenia: An 8week, randomized, double-blind, placebo-controlled trial［J］. Clin Schizophr Relat Psychoses, 2018,12(1):31-41.
［41］Frau R, Bini V, Soggiu A, et al. The neurosteroidogenic enzyme 5 alpha-reductase mediates psychotic-Like complications of sleep deprivation［J］. Neuropsychopharmacology, 2017,42(11):2196-2205.
［42］Huang Y, Hung C, Lin P, et al. Gender differences in susceptibility to schizophrenia: potential implication of neurosteroids［J］. Psychoneuroendocrinology, 84:87-93.
［43］Moore L, Kyaw M, Vercammen A, et al. Serum testosterone levels are related to cognitive function in men with schizophrenia［J］. Psychoneuroendocrinology, 2013,38(9):1717-1728.

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