PDF(Pubmed)
Abstract：
Clozapine is listed as one of the most effective antipsychotics and has been approved for treating treatment-resistant schizophrenia (TRS); however, several type A and B adverse reactions, including weight gain, metabolic complications, cardiotoxicity, convulsions, and discontinuation syndromes, exist. The critical mechanisms of clinical efficacy for schizophrenia, TRS, and adverse reactions of clozapine have not been elucidated. Recently, the GABA isomer L-β-aminoisobutyric acid (L-BAIBA), a protective myokine in the peripheral organs, was identified as a candidate novel transmission modulator in the central nervous system (CNS). L-BAIBA activates adenosine monophosphate-activated protein kinase (AMPK) signalling in both the peripheral organs and CNS. Activated AMPK signalling in peripheral organs is an established major target for treating insulin-resistant diabetes, whereas activated AMPK signalling in the hypothalamus contributes to the pathophysiology of weight gain and metabolic disturbances. Clozapine increases L-BAIBA synthesis in the hypothalamus. In addition, the various functions of L-BAIBA in the CNS have recently been elucidated, including as an activator of GABA-B and group-III metabotropic glutamate (III-mGlu) receptors. Considering the expressions of GABA-B and III-mGlu receptors (localised in the presynaptic regions), the activation of GABA-B and III-mGlu receptors can explain the distinct therapeutic advantages of clozapine in schizophrenia or TRS associated with N-methyl-D-aspartate (NMDA) receptor disturbance compared with other atypical antipsychotics via the inhibition of the persistent tonic hyperactivation of thalamocortical glutamatergic transmission in the prefrontal cortex. L-BAIBA has also been identified as a gliotransmitter, and a detailed exploration of the function of L-BAIBA in tripartite synaptic transmission can further elucidate the pathophysiology of effectiveness for treating TRS and/or specific adverse reactions of clozapine.
摘要：
氯氮平被列为最有效的抗精神病药物之一，已被批准用于治疗难治性精神分裂症（TRS）；然而，几种A型和B型不良反应，包括体重增加,代谢并发症,心脏毒性,抽搐,和停药综合征，存在。精神分裂症临床疗效的关键机制，TRS,氯氮平的不良反应尚未阐明。最近,GABA异构体L-β-氨基异丁酸（L-BAIBA），外周器官中的保护性肌动蛋白，被确定为中枢神经系统（CNS）中的候选新型传输调节剂。L-BAIBA激活外周器官和CNS中的一磷酸腺苷活化蛋白激酶(AMPK)信号传导。外周器官中激活的AMPK信号是治疗胰岛素抵抗糖尿病的既定主要目标。而下丘脑中激活的AMPK信号有助于体重增加和代谢紊乱的病理生理学。氯氮平增加下丘脑中L-BAIBA的合成。此外,最近已经阐明了L-BAIBA在中枢神经系统中的各种功能，包括作为GABA-B和III组代谢型谷氨酸（III-mGlu）受体的激活剂。考虑到GABA-B和III-mGlu受体的表达（位于突触前区域），与其他非典型抗精神病药物相比,GABA-B和III-mGlu受体的激活可以解释氯氮平在精神分裂症或与N-甲基-D-天冬氨酸(NMDA)受体相关的TRS障碍中的独特治疗优势,其通过抑制前额叶皮层丘脑皮质谷氨酸能传递的持续强直过度激活。L-BAIBA也被确定为胶质细胞分泌，详细探讨L-BAIBA在三部分突触传递中的功能可以进一步阐明治疗TRS的有效性和/或氯氮平的特定不良反应的病理生理学。
