Sapolsky R M, Packan D R, Vale W W
Department of Biological Sciences, Stanford University, CA 94305.
Brain Res. 1988 Jun 21;453(1-2):367-71. doi: 10.1016/0006-8993(88)90180-1.
Glucocorticoids (GCs) disrupt the energy metabolism of neurons of the hippocampus, and thus leave them more vulnerable to a variety of damaging metabolic insults. In this manner, GCs appear to influence the rate of hippocampal neuron loss during aging in the rat, as well as the severity of hippocampal damage following hypoxia-ischemia or seizure. These GC actions could be secondary to their multitudinous peripheral actions. The present report, however, suggests that GCs directly endanger hippocampal neurons. Glucocorticoid-induced sensitization of neurons to damaging toxins was demonstrated in vitro. The viability of primary cultures of dispersed fetal rat hippocampal neurons was assessed following exposure to a variety of neurotoxins. Prior incubation of the cultures with the rodent-typical GC, corticosterone, significantly decreased neuronal viability in the face of the toxins. Such compounds included the glutaminergic excitotoxin kainic acid, the antimetabolite 3-acetylpyridine and the superoxide radical generator paraquat. As little as 10(-9) M corticosterone could potentiate damage, a concentration equivalent to low basal values in vivo. Higher concentrations of corticosterone could potentiate damage even further; these corticosterone concentrations were not themselves damaging. Administration of glucose increased neuronal viability in the face of the GC/toxin combination, without increasing viability following toxin alone. This suggests that a critical feature of the action of GCs on neurons might be the inhibition of glucose utilization (which is a hallmark of peripheral GC action).
糖皮质激素（GCs）会扰乱海马体神经元的能量代谢，从而使它们更容易受到各种有害代谢损伤的影响。通过这种方式，GCs似乎会影响大鼠衰老过程中海马体神经元的损失速度，以及缺氧缺血或癫痫发作后海马体损伤的严重程度。这些GC的作用可能是其众多外周作用的继发结果。然而，本报告表明，GCs会直接危及海马体神经元。在体外实验中证实了糖皮质激素诱导的神经元对损伤性毒素的敏感性。在暴露于多种神经毒素后，评估了分散的胎鼠海马体神经元原代培养物的活力。在用典型的啮齿动物GC——皮质酮对培养物进行预先孵育后，面对毒素时神经元活力显著降低。这些毒素包括谷氨酰胺能兴奋性毒素海人酸、抗代谢物3-乙酰吡啶和超氧自由基生成剂百草枯。低至10^(-9) M的皮质酮就能增强损伤，这一浓度相当于体内的低基础值。更高浓度的皮质酮能进一步增强损伤；这些皮质酮浓度本身并无损伤作用。给予葡萄糖可提高面对GC/毒素组合时的神经元活力，但单独给予毒素时则不会提高活力。这表明GCs对神经元作用中的一个关键特征可能是对葡萄糖利用的抑制（这是外周GC作用的一个标志）。
