Zeevalk G D, Bernard L P, Sinha C, Ehrhart J, Nicklas W J
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Neurology, Piscataway, N.J., USA.
Dev Neurosci. 1998;20(4-5):444-53. doi: 10.1159/000017342.
Glutamate receptor involvement and oxidative stress have both been implicated in damage to neurons due to impairment of energy metabolism. Using two different neuronal in vitro model systems, an ex vivo chick retinal preparation and dopamine neurons in mesencephalic culture, the involvement and interaction of these events as early occurring contributors to irreversible neuronal damage have been examined. Consistent with previous reports, the early acute changes in the retinal preparation, as well as irreversible loss of dopamine neurons due to inhibition of metabolism, can be prevented by blocking NMDA receptors during the time of energy inhibition. Oxidative stress was suggested to be a downstream consequence and contributor to neuronal cell loss due to either glutamate receptor overstimulation or metabolic inhibition since trapping of free radicals with the cyclic nitrone spin-trapping agent MDL 102,832 (1 mM) attenuated acute excitotoxicity in the retinal preparation or loss of mesencephalic dopamine neurons due to either metabolic inhibition by the succinate dehydrogenase inhibitor, malonate, or exposure to excitotoxins. In mesencephalic culture, malonate caused an enhanced efflux of both oxidized and reduced glutathione into the medium, a significant reduction in total reduced glutathione and a significant increase in total oxidized glutathione at time points that preceded those necessary to cause toxicity. These findings provide direct evidence for early oxidative events occurring following malonate exposure and suggest that the glutathione system is important for protecting neurons during inhibition of energy metabolism. Consistent with this, lowering of glutathione by buthionine sulfoxamine (BSO) pretreatment greatly potentiated malonate toxicity in the mesencephalic dopamine population. In contrast, BSO pretreatment did not potentiate glutamate toxicity. This latter finding indicates dissimilarities in the type of oxidative stress that is generated by the two insults and suggests that the oxidative challenge during energy inhibition is not solely a downstream consequence of glutamate receptor overstimulation.
谷氨酸受体参与和氧化应激均与能量代谢受损导致的神经元损伤有关。使用两种不同的体外神经元模型系统，即离体鸡视网膜制剂和中脑培养中的多巴胺神经元，研究了这些事件作为不可逆神经元损伤早期促成因素的参与情况和相互作用。与先前的报道一致，在能量抑制期间阻断NMDA受体可以预防视网膜制剂中的早期急性变化以及由于代谢抑制导致的多巴胺神经元不可逆损失。氧化应激被认为是谷氨酸受体过度刺激或代谢抑制导致神经元细胞损失的下游后果和促成因素，因为用环状硝酮自旋捕获剂MDL 102,832（1 mM）捕获自由基可减轻视网膜制剂中的急性兴奋性毒性或中脑多巴胺神经元因琥珀酸脱氢酶抑制剂丙二酸的代谢抑制或暴露于兴奋性毒素而导致的损失。在中脑培养中，丙二酸导致氧化型和还原型谷胱甘肽向培养基中的流出增加，总还原型谷胱甘肽显著减少，总氧化型谷胱甘肽在导致毒性所需时间点之前显著增加。这些发现为丙二酸暴露后早期氧化事件提供了直接证据，并表明谷胱甘肽系统在能量代谢抑制期间对保护神经元很重要。与此一致的是，丁硫氨酸亚砜胺（BSO）预处理降低谷胱甘肽水平大大增强了丙二酸对中脑多巴胺群体的毒性。相比之下，BSO预处理并未增强谷氨酸毒性。后一发现表明两种损伤产生的氧化应激类型存在差异，并表明能量抑制期间的氧化挑战并非仅仅是谷氨酸受体过度刺激的下游后果。
