Evaluation of the protective effect of oestradiol against toxicity induced by 6-hydroxydopamine and 1-methyl-4-phenylpyridinium ion (MPP+) towards dopaminergic mesencephalic neurones in primary culture
Evaluation of the protective effect of oestradiol against toxicity induced by 6-hydroxydopamine and 1-methyl-4-phenylpyridinium ion (MPP+) towards dopaminergic mesencephalic neurones in primary culture
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DOI：
10.1046/j.0022-3042.2001.00693.x
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发表时间：
2002-01-01
影响因子：
4.7
通讯作者：
Pelaprat, D
中科院分区：
文献类型：
--
作者：
Callier, S;Le Saux, M;Pelaprat, D
最近的研究结果表明，性腺类固醇激素具有神经保护作用，并可能在延缓帕金森病的发展方面提供临床益处。在本报告中，我们研究了雌二醇保护在无血清或添加血清的培养基中培养的中脑多巴胺能神经元免受 6-羟基多巴胺或 1-甲基-4-苯基吡啶鎓离子 (MPP+) 诱导的毒性的能力。通过酪氨酸羟化酶 (TH) 免疫细胞化学、[3 H]多巴胺 ([H-3]DA) 摄取、多巴胺能过程长度和乳酸脱氢酶 (LDH) 释放测量来评估毒素和雌二醇的效率。在补充血清的培养基中生长的培养物中，用高浓度（10-100μm）17β-雌二醇或17α-雌二醇（具有弱雌激素活性的立体异构体）预处理2小时，可以保护多巴胺能和非多巴胺能神经元免受6-羟基多巴胺（6-OHDA；40或100 pm）和高浓度诱导的毒性。在这些培养条件下获得显着神经元死亡所需的 MPP+ 浓度（50 克）。在这些浓度下，MPP+不再对多巴胺能神经元具有选择性，而是影响培养物中存在的所有细胞。相比之下，激素治疗不能防止由较低 MPP+ 浓度（低于 10 mum）诱导的多巴胺能神经元选择性变性，这与呼吸链复合物 I 的抑制有关。在无血清培养基中生长的培养物中，雌二醇浓度高于 1 mum 会诱导神经元变性，并且在较低浓度的类固醇下没有观察到针对 6-OHDA 或 MPP+ 毒性的保护作用。该模型中证明的 17α- 或 17β-雌二醇的神经保护作用可能是由于这些化合物的抗氧化特性。然而，不能排除类固醇的其他非基因组效应。
Recent findings suggest that gonadal steroid hormones are neuroprotective and may provide clinical benefits in delaying the development of Parkinson's disease. In this report we investigated the ability of oestradiol to protect mesencephalic dopaminergic neurones cultured in serum-free or serum-supplemented medium from toxicity induced by 6-hydroxydopamine or 1-methyl-4-phenylpyridinium ion (MPP+). The efficiency of both toxins and oestradiol was evaluated by tyrosine hydroxylase (TH) immunocytochemistry, [3 H]dopamine ([H-3]DA) uptake, length of dopaminergic processes and lactate dehydrogenase (LDH) release measurement. In cultures grown in serum-supplemented medium, a 2-h pre-treatment with high concentrations (10-100 mum) of 17beta-oestradiol or 17alpha-oestradiol, the stereoisomer with weak oestrogenic activity, protected both dopaminergic and non-dopaminergic neurones from toxicity induced by 6-hydroxydopamine (6-OHDA; 40 or 100 pm) and by the high MPP+ concentrations (50 gm) necessary to obtain significant neuronal death under those culture conditions. At these concentrations, MPP+ was no longer selective for dopaminergic neurones but affected all cells present in the culture. In contrast, the hormonal treatments did not protect against selective degeneration of dopaminergic neurones induced by lower MPP+ concentrations (below 10 mum), related to inhibition of complex I of respiratory chain. In cultures grown in serum-free medium, oestradiol concentrations higher than 1 mum induced neuronal degeneration and no protection against 6-OHDA or MPP+ toxicity was observed at lower concentrations of the steroid. The neuroprotective effects of 17alpha- or 17beta-oestradiol evidenced in this model might be due to the antioxidant properties of these compounds. However, other non-genomic effects of the steroids cannot be excluded.