Zhang X, Boulton A A, Yu P H
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Eur J Neurosci. 1996 Jul;8(7):1432-40. doi: 10.1111/j.1460-9568.1996.tb01605.x.
The effect of MK-801, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, on the kainic acid-induced expression of the inducible heat shock protein 70 kDa (HSP70) and on neuronal death in the rat hippocampus was investigated. HSP70 is expressed in approximately 80% of the pyramidal neurons in the CA1 field 1 day after kainic acid injection. The majority of these HSP70-immunopositive neurons exhibited swelling and a hollow appearance in the perikaryon, indicating that they had been injured following kainic acid-elicited limbic seizures. Four days after administration of kainic acid, 87% of the pyramidal neurons in the CA1 field were dead. When a single dose of MK-801 was administered 1 h before kainic acid injection, the number of rats suffering with seizures was reduced, the severity of limbic seizures was attenuated and seizure onset was delayed. Neither HSP70 expression on day 1 nor neuronal loss on day 4 in the CA1 pyramidal cell layer was observed in these animals. A considerable number of HSP70-immunopositive neurons was detected in the dentate hilus, however, and somewhat fewer in the CA3a and CA3c subfields on day 1. Severe neuronal damage in these regions followed on day 4. Interestingly, little HSP70 expression or neuronal loss was observed in the CA3b subfield in these same animals. When a single dose of MK-801 was given 4 h after kainic acid treatment, HSP70 expression was partially blocked; 18% of neurons expressed HSP70 on day 1 and 37% on day 4 in CA1 pyramidal neurons in comparison to the kainic acid controls. About 50% neuronal death was detected in the CA1 pyramidal cell layer 4 days after kainic acid treatment followed by MK-801. When the animals were treated with MK-801 4 h after kainic acid treatment followed by additional daily administration for 3 days, a negligible number of pyramidal neurons expressed HSP70, and the survival of pyramidal cells was significantly increased in the CA1 field. Limbic seizure-induced HSP70 expression not only indicates neuronal injury in the pyramidal cell layer of the hippocampus but also predicts delayed neuronal death, at least in the case of the CA1 field of animals that suffered stage IV-V seizures.
研究了非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂MK-801对海藻酸诱导的大鼠海马中诱导型70 kDa热休克蛋白（HSP70）表达及神经元死亡的影响。海藻酸注射1天后，CA1区约80%的锥体细胞表达HSP70。这些HSP70免疫阳性神经元大多在胞体出现肿胀和空洞样外观，表明它们在海藻酸诱发的边缘性癫痫发作后受到了损伤。海藻酸给药4天后，CA1区87%的锥体细胞死亡。在海藻酸注射前1小时给予单剂量的MK-801，癫痫发作的大鼠数量减少，边缘性癫痫发作的严重程度减轻，发作起始延迟。在这些动物中，未观察到第1天CA1锥体细胞层的HSP70表达及第4天的神经元丢失。然而，在齿状回门区检测到相当数量的HSP70免疫阳性神经元，第1天在CA3a和CA3c亚区的数量略少。第4天这些区域出现严重的神经元损伤。有趣的是，在这些相同动物的CA3b亚区未观察到HSP70表达或神经元丢失。在海藻酸处理后4小时给予单剂量的MK-801，HSP70表达被部分阻断；与海藻酸对照组相比，CA1锥体细胞中第1天18%的神经元表达HSP70，第4天为37%。海藻酸处理后给予MK-801，4天后在CA1锥体细胞层检测到约50%的神经元死亡。当动物在海藻酸处理后4小时用MK-801治疗并随后每天额外给药3天，表达HSP70的锥体细胞数量可忽略不计，且CA1区锥体细胞的存活率显著增加。边缘性癫痫发作诱导的HSP70表达不仅表明海马锥体细胞层的神经元损伤，而且至少在遭受IV-V期癫痫发作的动物的CA1区，还可预测延迟性神经元死亡。
