Callier Sophie, Le Saux Maryvonne, Lhiaubet Anne-Marie, Di Paolo Thérèse, Rostène William, Pelaprat Didier
Unité 339 INSERM, Hôpital Saint Antoine, Paris, France.
J Neurochem. 2002 Jan;80(2):307-16. doi: 10.1046/j.0022-3042.2001.00693.x.
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, [3H]dopamine ([3H]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 microM) 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 microM) and by the high MPP+ concentrations (50 microM) 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 microM), related to inhibition of complex I of respiratory chain. In cultures grown in serum-free medium, oestradiol concentrations higher than 1 microM 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.
近期研究结果表明，性腺甾体激素具有神经保护作用，可能在延缓帕金森病的发展方面带来临床益处。在本报告中，我们研究了雌二醇对在无血清或含血清培养基中培养的中脑多巴胺能神经元的保护能力，这些神经元会受到6-羟基多巴胺或1-甲基-4-苯基吡啶离子（MPP⁺）诱导的毒性影响。通过酪氨酸羟化酶（TH）免疫细胞化学、[³H]多巴胺（[³H]DA）摄取、多巴胺能突起长度以及乳酸脱氢酶（LDH）释放测量来评估两种毒素和雌二醇的作用效果。在含血清培养基中生长的培养物中，用高浓度（10 - 100微摩尔）的17β-雌二醇或17α-雌二醇（具有弱雌激素活性的立体异构体）进行2小时预处理，可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微摩尔）以及在这些培养条件下导致显著神经元死亡所需的高浓度MPP⁺（50微摩尔）诱导的毒性影响。在这些浓度下，MPP⁺不再对多巴胺能神经元具有选择性，而是影响培养物中所有细胞。相比之下，激素处理不能保护免受较低浓度MPP⁺（低于10微摩尔）诱导的多巴胺能神经元选择性退化，这与呼吸链复合体I的抑制有关。在无血清培养基中生长的培养物中，高于1微摩尔的雌二醇浓度会诱导神经元退化，在较低浓度的类固醇下未观察到对6-OHDA或MPP⁺毒性的保护作用。在该模型中证实的17α-或17β-雌二醇的神经保护作用可能归因于这些化合物的抗氧化特性。然而，类固醇的其他非基因组效应也不能排除。
