Sawada H, Ibi M, Kihara T, Urushitani M, Akaike A, Shimohama S
Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
J Neurosci Res. 1998 Dec 1;54(5):707-19. doi: 10.1002/(SICI)1097-4547(19981201)54:5<707::AID-JNR16>3.0.CO;2-T.
Oxidative stress is important in the process of dopaminergic neuronal degeneration in Parkinson's disease. Recent studies suggest that estrogens have neuroprotective effects in neurodegenerative disorders, including Alzheimer's disease. In the present study, we investigated neuroprotection against oxidative stress afforded by estradiol using primary neuronal culture of the rat ventral mesencephalon. Oxidative stress induced by glutamate, superoxide anions, and hydrogen peroxide caused significant neuronal death. Although simultaneous administration of 17beta-estradiol and glutamate did not show any significant effects, preincubation with 17beta-estradiol provided significant neuroprotection against glutamate-induced neurotoxicity (ED50 was 50 microM for dopaminergic and 15 microM for nondopaminergic neurons). Neuroprotection occurred even after a brief preincubation with 17beta-estradiol and was not significantly blocked by either an estrogen receptor antagonist or a protein synthesis inhibitor. These findings indicate that the neuroprotection against glutamate neurotoxicity is mediated by neither estrogen receptors nor activation of genome transcription. Other steroids (corticosterone, testosterone, and cholesterol) did not provide significant neuroprotection against glutamate-induced neurotoxicity. Furthermore, preincubation with 17beta-estradiol provided neuroprotection against neuronal death induced by both superoxide anions and hydrogen peroxide. Dichlorofluorescin diacetate, a marker of oxygen radicals, revealed that preincubation with 17beta-estradiol suppressed intracellular oxygen radicals induced by hydrogen peroxide. The biologically inactive stereoisomer of estradiol, 17alpha-estradiol, provided neuroprotection against glutamate-induced toxicity in dopaminergic neurons, as well as the 17beta isoform. 17Alpha-estradiol may be a potential therapeutic agent used to prevent dopaminergic neuronal death induced by oxidative stress in Parkinson's disease.
氧化应激在帕金森病多巴胺能神经元变性过程中起重要作用。最近的研究表明，雌激素在包括阿尔茨海默病在内的神经退行性疾病中具有神经保护作用。在本研究中，我们使用大鼠腹侧中脑原代神经元培养物研究了雌二醇对氧化应激的神经保护作用。谷氨酸、超氧阴离子和过氧化氢诱导的氧化应激导致显著的神经元死亡。虽然同时给予17β-雌二醇和谷氨酸没有显示出任何显著效果，但预先用17β-雌二醇孵育可提供显著的神经保护作用，防止谷氨酸诱导的神经毒性（多巴胺能神经元的ED50为50μM，非多巴胺能神经元为15μM）。即使在与17β-雌二醇短暂预孵育后也会出现神经保护作用，并且不受雌激素受体拮抗剂或蛋白质合成抑制剂的显著阻断。这些发现表明，对谷氨酸神经毒性的神经保护作用既不是由雌激素受体介导的，也不是由基因组转录激活介导的。其他类固醇（皮质酮、睾酮和胆固醇）对谷氨酸诱导的神经毒性没有提供显著的神经保护作用。此外，预先用17β-雌二醇孵育可提供神经保护作用，防止超氧阴离子和过氧化氢诱导的神经元死亡。二氯荧光素二乙酸酯是氧自由基的标志物，显示预先用17β-雌二醇孵育可抑制过氧化氢诱导的细胞内氧自由基。雌二醇的无生物活性立体异构体17α-雌二醇与17β异构体一样，对多巴胺能神经元的谷氨酸诱导毒性提供神经保护作用。17α-雌二醇可能是一种潜在的治疗药物，用于预防帕金森病中氧化应激诱导的多巴胺能神经元死亡。
