Kita Taizo, Wagner George C, Nakashima Toshikatsu
Department of Pharmacology, Nara Medical University, Nara, Japan.
J Pharmacol Sci. 2003 Jul;92(3):178-95. doi: 10.1254/jphs.92.178.
Methamphetamine (METH)-induced neurotoxicity is characterized by a long-lasting depletion of striatal dopamine (DA) and serotonin as well as damage to striatal dopaminergic and serotonergic nerve terminals. Several hypotheses regarding the mechanism underlying METH-induced neurotoxicity have been proposed. In particular, it is thought that endogenous DA in the striatum may play an important role in mediating METH-induced neuronal damage. This hypothesis is based on the observation of free radical formation and oxidative stress produced by auto-oxidation of DA consequent to its displacement from synaptic vesicles to cytoplasm. In addition, METH-induced neurotoxicity may be linked to the glutamate and nitric oxide systems within the striatum. Moreover, using knockout mice lacking the DA transporter, the vesicular monoamine transporter 2, c-fos, or nitric oxide synthetase, it was determined that these factors may be connected in some way to METH-induced neurotoxicity. Finally a role for apoptosis in METH-induced neurotoxicity has also been established including evidence of protection of bcl-2, expression of p53 protein, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), activity of caspase-3. The neuronal damage induced by METH may reflect neurological disorders such as autism and Parkinson's disease.
甲基苯丙胺（METH）诱导的神经毒性的特征是纹状体多巴胺（DA）和5-羟色胺长期耗竭，以及纹状体多巴胺能和5-羟色胺能神经末梢受损。关于METH诱导神经毒性的潜在机制，已经提出了几种假说。特别是，人们认为纹状体内的内源性DA可能在介导METH诱导的神经元损伤中起重要作用。这一假说基于以下观察结果：DA从突触小泡转移到细胞质后，其自身氧化会产生自由基形成和氧化应激。此外，METH诱导的神经毒性可能与纹状体内的谷氨酸和一氧化氮系统有关。此外，通过使用缺乏DA转运体、囊泡单胺转运体2、c-fos或一氧化氮合酶的基因敲除小鼠，确定这些因素可能在某种程度上与METH诱导的神经毒性有关。最后，细胞凋亡在METH诱导的神经毒性中的作用也已得到证实，包括bcl-2的保护证据、p53蛋白的表达、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）、caspase-3的活性。METH诱导的神经元损伤可能反映了诸如自闭症和帕金森病等神经疾病。
