Lorenz L, Dang J, Misiak M, Tameh Abolfazl A, Beyer C, Kipp M
Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
J Neuroendocrinol. 2009 Oct;21(10):841-9. doi: 10.1111/j.1365-2826.2009.01903.x. Epub 2009 Jul 21.
Oestrogens are powerful endogenous and exogenous neuroprotective hormones in animal models of brain injury, including focal cerebral ischaemia. This protective effect has been demonstrated under a variety of different treatments and injury paradigms, such as in vivo and in vitro stroke conditions. Neuroprotection in the central nervous system by progesterone is less defined. In the present study, cultured cortical and midbrain mouse neurones and human neuroblastoma cells (SH-SY5Y) were exposed to combined glucose-serum deprivation (CGSD), which is regarded as a reliable model mimicking the effects of ischaemia in vitro. Cell viability was assayed using lactate dehydrogenase release and metabolic activity. Conditions for CGSD treatment were chosen to yield half-maximal cell death rates. The validity of CGSD in vitro was compared with permanent middle cerebral artery occlusion (MCAO) in vivo. CGSD for 4 h induced half-maximal neuronal cell death. MCAO in vivo for the same period resulted in significant neuronal loss, also suggesting the validity of CGSD as a suitable stroke-like in vitro model. Combined steroid treatment (17beta-oestradiol and progesterone) but not the application of single steroids abolished CGSD-induced cell death of cortical neurones in vitro. By contrast, no cell protection was found in midbrain neurones or neuroblastoma cells. The co-application of oestrogen (ICI 182,780) or progesterone (RU-486) receptor antagonists did not obviously counteract the protective steroid effects. This suggests the operation of nonclassical steroid mechanisms and their implication in mediation of hormonal effects. The surplus of combined protective hormonal effects might be a result of the observed influence of progesterone application on neuronal oestradiol synthesis. The data obtained in the present study clearly highlight the potential of a combined steroid treatment under toxic degenerative brain pathologies.
在脑损伤动物模型（包括局灶性脑缺血）中，雌激素是强大的内源性和外源性神经保护激素。在各种不同的治疗方法和损伤模式下，如体内和体外中风条件下，这种保护作用都得到了证实。孕酮对中枢神经系统的神经保护作用尚不太明确。在本研究中，将培养的小鼠皮质和中脑神经元以及人神经母细胞瘤细胞（SH-SY5Y）暴露于联合葡萄糖-血清剥夺（CGSD），这被认为是一种在体外模拟缺血效应的可靠模型。使用乳酸脱氢酶释放和代谢活性来测定细胞活力。选择CGSD处理条件以产生半数最大细胞死亡率。将体外CGSD的有效性与体内永久性大脑中动脉闭塞（MCAO）进行比较。CGSD处理4小时可诱导半数最大神经元细胞死亡。同期体内MCAO导致显著的神经元损失，这也表明CGSD作为一种合适的体外类中风模型的有效性。联合类固醇治疗（17β-雌二醇和孕酮）可消除体外CGSD诱导的皮质神经元细胞死亡，而单一类固醇则无此作用。相比之下，在中脑神经元或神经母细胞瘤细胞中未发现细胞保护作用。雌激素（ICI 182,780）或孕酮（RU-486）受体拮抗剂的联合应用并未明显抵消类固醇的保护作用。这表明存在非经典类固醇机制及其在激素效应介导中的作用。联合保护性激素效应的过剩可能是观察到的孕酮应用对神经元雌二醇合成影响的结果。本研究获得的数据清楚地突出了联合类固醇治疗在毒性退行性脑病变中的潜力。
