Investigation of betaine as a novel psychotherapeutic for schizophrenia.
Investigation of betaine as a novel psychotherapeutic for schizophrenia.
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甜菜碱作为精神分裂症新型心理治疗药物的研究。
DOI：
10.1016/j.ebiom.2019.05.062
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Yoshikawa T
中科院分区：
文献类型：
--
作者：
Ohnishi T;Balan S;Toyoshima M;Maekawa M;Ohba H;Watanabe A;Iwayama Y;Fujita Y;Tan Y;Hisano Y;Shimamoto-Mitsuyama C;Nozaki Y;Esaki K;Nagaoka A;Matsumoto J;Hino M;Mataga N;Hayashi-Takagi A;Hashimoto K;Kunii Y;Kakita A;Yabe H;Yoshikawa T
背景甜菜碱具有抗多种生物应激的作用，据报道其水平在精神分裂症患者中降低。我们的目的是测试甜菜碱在精神分裂症病理生理学中的作用，并评估其作为一种新的精神治疗剂的潜力。（甜菜碱合成基因）缺陷小鼠和甜菜碱补充的近交系小鼠，我们评估了甜菜碱在精神病病理生理学中的作用，及其作为一种新型精神治疗剂的潜力，通过利用代谢组学，行为，发现Chdh-deficient小鼠揭示了残留的精神行为沿着与精神分裂症相关的分子扰动在大脑中。甜菜碱补充引起遗传背景依赖性的改善认知能力，并抑制甲基苯丙胺（MAP）诱导的行为敏化。此外，甜菜碱纠正MAP和体外苯环己哌啶（PCP）治疗引起的抗氧化和促炎反应的改变。甜菜碱对PCP所致的行为异常也有预防作用。值得注意的是，甜菜碱水平下降，在精神分裂症的尸检大脑，和共存的升高羰基应激，氧化应激的一种形式，划分了一个子集的精神分裂症与“甜菜碱缺乏-氧化应激病理”。我们揭示了在乙醛酸酶1（GLO 1）缺陷的hiPSC中甜菜碱水平的降低，其显示了升高的羰基应激，以及甜菜碱在减轻其方面的功效，从而支持甜菜碱和氧化应激条件之间的因果关系。此外，一个CHDH变异体rs35518479被鉴定为精神分裂症死后脑中CHDH表达的acis表达数量性状位点（QTL），允许基因型-本研究揭示了甜菜碱在精神病病理生理学中的作用，并强调了甜菜碱在精神分裂症亚群中的潜在益处。AMED脑科学研究计划（日本医学研究开发机构），批准号为JP 18 dm 0107083和JP 19 dm 0107083（TY）、JP 18 dm 0107129（MM）、JP 18 dm 0107086（YK）、JP 18 dm 0107107（HY）、JP 18 dm 0107104（AK）和JP 19 dm 0107119（KH），由日本文部科学省创新领域科学研究补助金资助，资助号为JP 18 H 05435（TY）、JP 18 H 05433（AH.- T）、JP18H05428（AH.- T和TY）和JP 16 H 06277（HY），以及JSPS KAKENHI在授权号JP 17 H 01574（TY）下获得的。此外，本研究还得到了新泻大学脑研究所合作研究项目（资助号2018-2809（YK））和RIKEN表观遗传学总统基金（100214-201801063606-340120）（TY）的支持。
BackgroundBetaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic.MethodsUsingChdh(a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses.FindingsTheChdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, aCHDHvariant, rs35518479, was identified as acis-expression quantitative trait locus (QTL) forCHDHexpression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy.InterpretationThe present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia.FundThis study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018–2809 (YK) and RIKEN Epigenetics Presidential Fund (100214–201801063606-340120) (TY).