Methamphetamine causes differential regulation of Bcl2

Bcl-2是一种线粒体内膜蛋白，可抑制神经元细胞凋亡。Bcl-2的表达通过减少活性氧的净细胞生成来抑制细胞死亡。不同研究人员的研究提供了无可挑剔的证据，证明氧基自由基在甲基苯丙胺（冰毒）诱导的神经毒性中起作用。此外，我们实验室的研究表明，在体外，过度表达Bcl-2的永生化大鼠神经元细胞可以保护其免受甲基安非他命诱导的凋亡。此外，安非他明可以引起原代皮质细胞培养中Bcl-X剪接变体表达的差异变化。这些观察结果表明，当给啮齿动物服用甲基苯丙胺时，也可能引起bcl -2相关基因的扰动。因此，本研究旨在确定甲基安非他明的使用是否确实与小鼠大脑中bcl -2相关基因表达的转录和翻译变化有关。在这里，我们报告了甲基安非他明的毒性方案确实导致了促死亡Bcl-2家族基因BAD、BAX和BID的显著增加。同时，抗死亡基因Bcl-2和Bcl-XL显著降低。因此，这些结果支持了这样一种观点，即注射有毒剂量的甲基苯丙胺会触发哺乳动物大脑中程序性死亡途径的激活。

Bcl-2, an inner mitochondrial membrane protein, inhibits apoptotic neuronal cell death. Expression of Bcl-2 inhibits cell death by decreasing the net cellular generation of reactive oxygen species. Studies by different investigators have provided unimpeachable evidence of a role for oxygen-based free radicals in methamphetamine (METH) -induced neurotoxicity. In addition, studies from our laboratory have shown that immortalized rat neuronal cells that overexpress Bcl-2 are protected against METH-induced apoptosis in vitro. Moreover, the amphetamines can cause differential changes in the expression of Bcl-X splice variants in primary cortical cell cultures. These observations suggested that METH might also cause perturbations of Bcl-2-related genes when administered to rodents. Thus, the present study was conducted to determine whether the use of METH might indeed be associated with transcriptional and translational changes in the expression of Bcl-2-related genes in the mouse brain. Here we report that a toxic regimen of METH did cause significant increases in the pro-death Bcl-2 family genes BAD, BAX, and BID. Concomitantly, there were significant decreases in the anti-death genes Bcl-2 and Bcl-XL. These results thus support the notion that injections of toxic doses of METH trigger the activation of the programmed death pathway in the mammalian brain.