Miyazaki Ikuko, Asanuma Masato, Diaz-Corrales Francisco J, Fukuda Masaya, Kitaichi Kiyoyuki, Miyoshi Ko, Ogawa Norio
Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
FASEB J. 2006 Mar;20(3):571-3. doi: 10.1096/fj.05-4996fje. Epub 2006 Jan 10.
Recently, the neurotoxicity of dopamine (DA) quinone formation by auto-oxidation of DA has focused on dopaminergic neuron-specific oxidative stress. In the present study, we examined DA quinone formation in methamphetamine (METH)-induced dopaminergic neuronal cell death using METH-treated dopaminergic cultured CATH.a cells and METH-injected mouse brain. In CATH.a cells, METH treatment dose-dependently increased the levels of quinoprotein (protein-bound quinone) and the expression of quinone reductase in parallel with neurotoxicity. A similar increase in quinoprotein levels was seen in the striatum of METH (4 mg/kg X4, i.p., 2 h interval)-injected BALB/c mice, coinciding with reduction of DA transporters. Furthermore, pretreatment of CATH.a cells with quinone reductase inducer, butylated hydroxyanisole, significantly and dose-dependently blocked METH-induced elevation of quinoprotein, and ameliorated METH-induced cell death. We also showed the protective effect of tyrosinase, which rapidly oxidizes DA and DA quinone to form stable melanin, against METH-induced dopaminergic neurotoxicity in vitro and in vivo using tyrosinase null mice. Our results indicate that DA quinone formation plays an important role, as a dopaminergic neuron-specific neurotoxic factor, in METH-induced neurotoxicity, which is regulated by quinone formation-related molecules.
最近，多巴胺（DA）通过自身氧化形成醌的神经毒性已聚焦于多巴胺能神经元特异性氧化应激。在本研究中，我们使用经甲基苯丙胺（METH）处理的多巴胺能培养CATH.a细胞和注射METH的小鼠脑，研究了METH诱导的多巴胺能神经元细胞死亡过程中DA醌的形成。在CATH.a细胞中，METH处理剂量依赖性地增加了醌蛋白（蛋白结合醌）水平和醌还原酶的表达，同时伴有神经毒性。在注射METH（4mg/kg×4，腹腔注射，间隔2小时）的BALB/c小鼠纹状体中也观察到醌蛋白水平有类似升高，这与多巴胺转运体的减少相一致。此外，用醌还原酶诱导剂丁基羟基茴香醚预处理CATH.a细胞，可显著且剂量依赖性地阻断METH诱导的醌蛋白升高，并改善METH诱导的细胞死亡。我们还利用酪氨酸酶基因敲除小鼠，在体外和体内证明了酪氨酸酶（其能快速氧化DA和DA醌以形成稳定的黑色素）对METH诱导的多巴胺能神经毒性具有保护作用。我们的结果表明，DA醌的形成作为一种多巴胺能神经元特异性神经毒性因子，在METH诱导的神经毒性中起重要作用，且该过程受醌形成相关分子的调节。
