Stein B A, Sapolsky R M
Department of Biological Sciences, Stanford University, CA 94305.
Brain Res. 1988 Nov 8;473(1):175-80. doi: 10.1016/0006-8993(88)90332-0.
Glucocorticoids (GCs), the adrenal steroids secreted during stress, have numerous catabolic effects which include damage to neurons of the hippocampus, a principal neural target site for the steroids. In the rat, the extent of GC exposure over the lifespan is a major determinant of the rate of hippocampal neuron death during aging. GCs also modulate the severity of hippocampal damage in the rat following insults such as seizure or hypoxia-ischemia. As evidence, exogenous GCs exacerbate, while adrenalectomy attenuates hippocampal damage after these insults. Thus, it is possible that diminution of endogenous GC secretion might protect the human hippocampus after similar neurological insults; adrenalectomy under such circumstances is obviously not a viable clinical option. We demonstrate the protective effects of transient chemical adrenalectomy with the GC synthesis inhibitor, metyrapone. Rats were microinfused with the excitotoxin kainic acid in order to induce status epilepticus seizures; this insult caused a significant GC stress-response. Attenuation of that response with metyrapone reduced the CA3 hippocampal damage produced by kainic acid. Metyrapone did not change the intensity of seizures, but rather, apparently, changed the capacity of neurons to withstand the seizure. Thus, metyrapone, which is used safely and efficaciously in other clinical contexts, might prove protective of the brain following seizure in the human.
糖皮质激素（GCs）是应激期间分泌的肾上腺类固醇，具有多种分解代谢作用，包括对海马神经元的损伤，海马是这些类固醇的主要神经靶位点。在大鼠中，一生中糖皮质激素暴露的程度是衰老过程中海马神经元死亡速率的主要决定因素。糖皮质激素还会调节大鼠在遭受癫痫发作或缺氧缺血等损伤后海马损伤的严重程度。有证据表明，外源性糖皮质激素会加剧损伤，而肾上腺切除则会减轻这些损伤后的海马损伤。因此，内源性糖皮质激素分泌减少可能会在类似的神经损伤后保护人类海马体；在这种情况下进行肾上腺切除术显然不是一个可行的临床选择。我们证明了用糖皮质激素合成抑制剂美替拉酮进行短暂化学性肾上腺切除的保护作用。给大鼠微量注射兴奋性毒素海藻酸以诱发癫痫持续状态；这种损伤引起了显著的糖皮质激素应激反应。美替拉酮减弱这种反应可减少海藻酸引起的海马CA3区损伤。美替拉酮并没有改变癫痫发作的强度，而是显然改变了神经元抵抗癫痫发作的能力。因此，在其他临床情况下安全有效使用的美替拉酮，可能对人类癫痫发作后的大脑具有保护作用。
