Keller J N, Huang F F, Dimayuga E R, Maragos W F
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Free Radic Biol Med. 2000 Nov 15;29(10):1037-42. doi: 10.1016/s0891-5849(00)00412-3.
The autoxidation and enzymatic catabolism of dopamine results in the generation of reactive oxygen species (ROS), which may possibly contribute to oxidative stress in multiple neurodegenerative disorders. Recent studies indicate that proteasome inhibition occurs in numerous neurodegenerative conditions, possibly as the result of oxidative stress, although the effects of dopamine on proteasome activity have not been determined. In the present study we examined the effects of dopamine on proteasome activity in the neural PC12 cell line. Application of dopamine induced a dose- and time-dependent decrease in proteasome activity, which occurred prior to cell death. Application of an antioxidant (gluthathione monoethyl ester), monoamine oxidase inhibitors (deprenyl, clogyline, paragyline), or an inhibitor of dopamine uptake (nomifensine) attenuated dopamine toxicity and dopamine-induced proteasome impairment. Application of the proteasome inhibitor lactacystin increased the toxicity of dopamine and the levels of protein oxidation following administration of dopamine. Together, these data indicate that dopamine induces proteasome inhibition that is dependent, in part, on ROS and dopamine uptake, and suggest a possible role for proteasome inhibition in dopamine toxicity.
多巴胺的自氧化和酶促分解代谢会产生活性氧（ROS），这可能在多种神经退行性疾病中导致氧化应激。最近的研究表明，蛋白酶体抑制在许多神经退行性疾病中都会发生，可能是氧化应激的结果，尽管多巴胺对蛋白酶体活性的影响尚未确定。在本研究中，我们检测了多巴胺对神经PC12细胞系中蛋白酶体活性的影响。多巴胺的应用导致蛋白酶体活性呈剂量和时间依赖性降低，这发生在细胞死亡之前。应用抗氧化剂（谷胱甘肽单乙酯）、单胺氧化酶抑制剂（司来吉兰、氯吉兰、帕吉林）或多巴胺摄取抑制剂（诺米芬辛）可减轻多巴胺毒性和多巴胺诱导的蛋白酶体损伤。蛋白酶体抑制剂乳胞素的应用增加了多巴胺的毒性以及多巴胺给药后蛋白质氧化水平。这些数据共同表明，多巴胺诱导的蛋白酶体抑制部分依赖于ROS和多巴胺摄取，并提示蛋白酶体抑制在多巴胺毒性中可能发挥作用。
