Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy.
Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy.
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雷帕霉素的机制/哺乳动物靶标和抗精神病药物的副作用：深入了解机制和治疗意义
DOI：
10.1038/s41398-021-01778-w
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发表时间：
2022-01-10
影响因子：
6.8
通讯作者：
Zhou C
中科院分区：
文献类型：
--
作者：
Zhuo C;Xu Y;Hou W;Chen J;Li Q;Liu Z;Dou G;Sun Y;Li R;Ma X;Tian H;Zhou C
抗精神病药物治疗已被广泛推荐为治疗急性精神分裂症和其他精神疾病的精神病性症状的标准治疗。然而，人们越来越关注抗精神病药物引起的副作用，包括体重增加、代谢综合征（MetS）和锥体外系运动障碍，这些副作用不仅降低患者依从性，而且易患糖尿病和心血管疾病。迄今为止，大多数关于抗精神病药物诱导的代谢副作用机制的研究和综述都集中在中枢神经系统对食欲和食物摄入的介导上。然而，抗精神病药物引起的糖脂代谢紊乱和肝脂肪变性可能先于体重增加和代谢综合征。最近的研究表明，雷帕霉素（mTOR）通路的机制/哺乳动物靶点在抗精神病药物诱导的肝葡萄糖和脂质代谢紊乱的病理生理学中起着关键的调节作用。此外，抗精神病药物促进纹状体mTOR通路激活，这有助于锥体外系运动副作用。虽然最近的研究结果促进了对mTOR通路在抗精神病药物引起的副作用中的作用的理解，但很少有人对这一新兴主题进行综述。在这篇综述中，我们分别通过关注肝脏和纹状体mTOR通路在代谢和锥体外系副作用发病机制中的作用来综合关键发现。我们进一步讨论了用mTOR特异性抑制剂使过度mTOR通路活化正常化的潜在治疗益处。对发病机制的更深入了解可能会为未来的干预策略提供信息，这些策略使用mTOR的药理学或遗传抑制剂来预防和管理抗精神病药物引起的副作用。
Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.
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影响因子：
--
作者：
Chen KC;Lee WY;Chen HY;Chen CY
通讯作者：
Chen CY
影响因子：
3.7
作者：
Girault, Elodie M.;Alkemade, Anneke;Kalsbeek, Andries
通讯作者：
Kalsbeek, Andries
影响因子：
7.3
作者：
Bowling H;Zhang G;Bhattacharya A;Pérez-Cuesta LM;Deinhardt K;Hoeffer CA;Neubert TA;Gan WB;Klann E;Chao MV
通讯作者：
Chao MV
影响因子：
3.5
作者：
Fu W;Hall MN
通讯作者：
Hall MN
影响因子：
16
作者：
Düvel K;Yecies JL;Menon S;Raman P;Lipovsky AI;Souza AL;Triantafellow E;Ma Q;Gorski R;Cleaver S;Vander Heiden MG;MacKeigan JP;Finan PM;Clish CB;Murphy LO;Manning BD
通讯作者：
Manning BD