Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
Neuropharmacology. 2011 Sep;61(4):677-86. doi: 10.1016/j.neuropharm.2011.05.010. Epub 2011 May 27.
High doses of methamphetamine induce the excessive release of dopamine resulting in neurotoxicity. However, moderate activation of dopamine receptors can promote neuroprotection. Therefore, we used in vitro and in vivo models of stroke to test the hypothesis that low doses of methamphetamine could induce neuroprotection. We demonstrate that methamphetamine does induce a robust, dose-dependent, neuroprotective response in rat organotypic hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD). A similar dose dependant neuroprotective effect was observed in rats that received an embolic middle cerebral artery occlusion (MCAO). Significant improvements in behavioral outcomes were observed in rats when methamphetamine administration delayed for up to 12 h after MCAO. Methamphetamine-mediated neuroprotection was significantly reduced in slice cultures by the addition of D1 and D2 dopamine receptor antagonist. Treatment of slice cultures with methamphetamine resulted in the dopamine-mediated activation of AKT in a PI3K dependant manner. A similar increase in phosphorylated AKT was observed in the striatum, cortex and hippocampus of methamphetamine treated rats following MCAO. Methamphetamine-mediated neuroprotection was lost in rats when PI3K activity was blocked by wortmannin. Finally, methamphetamine treatment decreased both cleaved caspase 3 levels in slice cultures following OGD and TUNEL staining within the striatum and cortex in rats following transient MCAO. These data indicate that methamphetamine can mediate neuroprotection through activation of a dopamine/PI3K/AKT-signaling pathway.
大剂量甲基苯丙胺会导致多巴胺过度释放，从而引发神经毒性。然而，多巴胺受体的适度激活可以促进神经保护。因此，我们使用体外和体内中风模型来检验低剂量甲基苯丙胺可能诱导神经保护的假设。我们证明，在暴露于氧葡萄糖剥夺（OGD）的大鼠器官型海马切片培养物中，甲基苯丙胺确实会引起强烈的、剂量依赖性的神经保护反应。在接受栓塞性大脑中动脉闭塞（MCAO）的大鼠中观察到类似的剂量依赖性神经保护作用。当甲基苯丙胺给药延迟至 MCAO 后 12 小时时，大鼠的行为结果得到了显著改善。在切片培养物中，添加 D1 和 D2 多巴胺受体拮抗剂可显著减少甲基苯丙胺介导的神经保护作用。用甲基苯丙胺处理切片培养物会导致 AKT 在 PI3K 依赖性方式下被多巴胺激活。在 MCAO 后，用甲基苯丙胺处理的大鼠的纹状体、皮质和海马中也观察到了类似的磷酸化 AKT 增加。当用 wortmannin 阻断 PI3K 活性时，大鼠的甲基苯丙胺介导的神经保护作用丧失。最后，在 OGD 后，甲基苯丙胺处理会降低切片培养物中 cleaved caspase 3 的水平，并且在短暂 MCAO 后，大鼠的纹状体和皮质中的 TUNEL 染色也会减少。这些数据表明，甲基苯丙胺可以通过激活多巴胺/PI3K/AKT 信号通路来介导神经保护作用。
