Kaasik A, Kalda A, Jaako K, Zharkovsky A
Department of Pharmacology, University of Tartu, 18 Ylikooli Street, 50090, Tartu, Estonia.
Neuroscience. 2001;102(2):427-32. doi: 10.1016/s0306-4522(00)00489-9.
Decreased levels of dehydroepiandrosterone sulphate have been hypothesized to contribute to increased vulnerability of the ageing or stressed human brain to ischemia. To help to address the question of whether of dehydroepiandrosterone sulphate has a possible neuroprotective effect against ischemic neuronal injury, we tested its effect on the neurodegeneration induced by oxygen-glucose deprivation in rat cultured cerebellar granule cells. Dehydroepiandrosterone sulphate added to the medium after injury demonstrated a neuroprotective effect with a median inhibitory concentration of 0.5 microM. At 10 microM concentration almost full neuroprotection was observed. Even more pronounced neuroprotective effect was found when dehydroepiandrosterone sulphate was added for 48h before injury. Furthermore, partial neuroprotection of dehydroepiandrosterone sulphate was also found against 1-methyl-4-phenylpyridinium, colchicine, glutamate and N-methyl-D-aspartate-induced toxicity. Further analysis demonstrated that dehydroepiandrosterone sulphate eliminated the apoptotic features of the oxygen-glucose deprivation-induced neuronal death: DNA fragmentation and nuclear condensation/fragmentation.Thus, our data suggest that dehydroepiandrosterone sulphate may have therapeutic potential in the prevention and treatment of ischemic/hypoxic neuronal damage. The neuroprotective action of dehydroepiandrosterone sulphate was inhibited by both a GABA(A) receptor-linked chloride channel agonist and an antagonist, pentobarbital and picrotoxin, respectively. It seems that GABA(A) receptor-mediated neuronal inhibition as well as neuronal excitation can reduce the neuroprotective action of dehydroepiandrosterone sulphate.
硫酸脱氢表雄酮水平降低被认为会导致衰老或应激状态下的人类大脑对缺血的易感性增加。为了探讨硫酸脱氢表雄酮是否对缺血性神经元损伤具有可能的神经保护作用，我们检测了其对大鼠培养小脑颗粒细胞氧糖剥夺诱导的神经变性的影响。损伤后添加到培养基中的硫酸脱氢表雄酮表现出神经保护作用，半数抑制浓度为0.5微摩尔。在10微摩尔浓度时观察到几乎完全的神经保护作用。当在损伤前48小时添加硫酸脱氢表雄酮时，发现神经保护作用更明显。此外，还发现硫酸脱氢表雄酮对1-甲基-4-苯基吡啶、秋水仙碱、谷氨酸和N-甲基-D-天冬氨酸诱导的毒性有部分神经保护作用。进一步分析表明，硫酸脱氢表雄酮消除了氧糖剥夺诱导的神经元死亡的凋亡特征：DNA片段化和核浓缩/碎片化。因此，我们的数据表明硫酸脱氢表雄酮在预防和治疗缺血/缺氧性神经元损伤方面可能具有治疗潜力。硫酸脱氢表雄酮的神经保护作用分别被GABA(A)受体相关的氯离子通道激动剂和拮抗剂戊巴比妥和印防己毒素所抑制。似乎GABA(A)受体介导的神经元抑制以及神经元兴奋均可降低硫酸脱氢表雄酮的神经保护作用。
