Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage.
Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage.
复制标题
DOI：
10.1017/s1461145708009802
复制
发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Manji HK
中科院分区：
文献类型：
--
作者：
Bachmann RF;Wang Y;Yuan P;Zhou R;Li X;Alesci S;Du J;Manji HK
越来越多的证据表明，线粒体功能障碍在各种神经退行性疾病和精神疾病的进展中发挥着关键作用。因此，增强线粒体功能可能有助于改善与各种神经精神疾病相关的神经可塑性和细胞弹性的损伤。一系列的研究进行了调查情绪稳定剂对线粒体功能的影响，并对脑介导的神经毒性。我们发现，锂和丙戊酸盐（VPA）的长期治疗增强了细胞呼吸速率。此外，锂或VPA的慢性处理增强了线粒体功能，如通过线粒体膜电位和SH-SY 5 Y细胞中的线粒体氧化所确定的。体内研究表明，锂或VPA的长期治疗可在线粒体水平上防止甲基苯丙胺（Meth）诱导的毒性。此外，这些药物阻止了线粒体细胞色素c、线粒体抗凋亡Bcl-2/Bax比值和线粒体细胞色素氧化酶（考克斯）活性的Meth-induced减少。Oligoarray分析表明，与细胞凋亡途径和线粒体功能相关的几种蛋白质的基因表达被改变的甲基，这些变化被削弱与锂或丙戊酸钠治疗。其中一个基因Bcl-2是锂和VPA的共同靶点。用特异性Bcl-2 siRNA敲低Bcl-2降低了锂和VPA诱导的线粒体氧化增加。这些发现表明，锂和VPA增强线粒体功能，并防止神经介导的毒性。这些药物可能在治疗与线粒体功能受损相关的其他疾病，如神经退行性疾病和精神分裂症中具有潜在的临床实用性。
Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.