Excitotoxic mechanisms of epileptic brain damage.
Excitotoxic mechanisms of epileptic brain damage.
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发表时间：
1986
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通讯作者：
J. Olney;Collins Rc;Sloviter Rs
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作者：
J. Olney;Collins Rc;Sloviter Rs
众所周知，假定的兴奋性神经递质谷氨酸 (Glu) 和天冬氨酸 (Asp) 是神经毒素，有可能通过兴奋机制破坏中枢神经元。红藻氨酸 (KA) 是一种 Glu 的刚性结构类似物，可强烈再现 Glu 对中枢神经元的兴奋性神经毒性（兴奋性毒性）作用，此外，还会导致大鼠持续性边缘系统癫痫发作和癫痫相关脑损伤模式，与人类癫痫中观察到的情况非常相似。在研究由 KA 引起的癫痫相关脑损伤综合征的过程中，我们观察到，由多种方法中的任何一种引起的持续癫痫活动都会导致类似类型的脑损伤。这些包括杏仁体内或硬膜上给予已知的惊厥药物，例如荷包牡丹碱、印防己毒素和叶酸，或全身给予通常不被视为惊厥药物的锂和胆碱能激动剂或胆碱酯酶抑制剂。我们进一步观察到，这种类型的脑损伤可以通过对穿通路径的持续电刺激在海马体中重现，穿通路径是海马体的主要兴奋性输入，被认为使用谷氨酸作为发射器。所有此类神经毒性过程的共同特征是，急性细胞病理学类似于由 Glu 或 Asp 诱导的兴奋性毒性类型的损伤，即树突的急性肿胀和神经元胞体的空泡变性，而轴突或轴突末端没有急性变化。我们发现，胆碱能药物诱发的癫痫脑损伤综合征可以通过阿托品预处理来预防，并且上述任何方法（胆碱能或非胆碱能药物）诱发的综合征可以分别通过地西泮预治疗或后治疗来预防或中止。我们在实验动物中的发现可以根据其与人类癫痫的潜在相关性来总结如下。如果持续超过 1 小时，持续的复杂部分性癫痫发作活动始终会导致细胞损伤。海马或阿蒙角硬化是主要的病理结果。因此，在人类癫痫治疗中，将癫痫发作活动控制在非常小的范围内可能是一个优先目标。该提案针对可能涉及的三种主要发射机系统进行了讨论；胆碱能、GABA能和谷氨酸/天冬氨酸。胆碱能系统可能在产生或维持这种类型的癫痫发作活动中发挥作用，抗胆碱能药物可以预防这种情况，只要在行为性癫痫发作之前给予抗胆碱能药物即可。（摘要截断为 400 字）
It is well established that the putative excitatory neurotransmitters, glutamate (Glu) and aspartate (Asp), are neurotoxins that have the potential of destroying central neurons by an excitatory mechanism. Kainic acid (KA), a rigid structural analog of Glu, powerfully reproduces the excitatory neurotoxic (excitotoxic) action of Glu on central neurons and, in addition, causes sustained limbic seizures and a pattern of seizure-linked brain damage in rats that closely resembles that observed in human epilepsy. In the course of studying the seizure-related brain damage syndrome induced by KA, we observed that a similar type of brain damage occurs as a consequence of sustained seizure activity induced by any of a variety of methods. These included intraamygdaloid or supradural administration of known convulsants such as bicuculline, picrotoxin and folic acid, or systemic administration of lithium and cholinergic agonists or cholinesterase inhibitors that have not commonly been viewed as convulsants. We have further observed that this type of brain damage can be reproduced in the hippocampus by persistent electrical stimulation of the perforant path, a major excitatory input to the hippocampus that is thought to use Glu as transmitter. It is a common feature of all such neurotoxic processes that the acute cytopathology resembles the excitotoxic type of damage induced by Glu or Asp, which is acute swelling of dendrites and vacuolar degeneration of neuronal soma, without acute changes in axons or axon terminals. We have found that the seizure-brain damage syndrome induced by cholinergic agents can be prevented by pretreatment with atropine and that the syndrome induced by any of the above methods, cholinergic or noncholinergic, can be either prevented or aborted respectively by either pre-or posttreatment with diazepam. Our findings in experimental animals may be summarized in terms of their potential relevance to human epilepsy as follows. Sustained complex partial seizure activity consistently results in cellular damage if allowed to continue for longer than 1 hr. Hippocampal, or Ammon's horn, sclerosis is the primary pathological result. It may be a priority goal, therefore, in the management of human epilepsy to control such seizure activity within very narrow limits. This proposal is discussed in terms of three major transmitter systems that may be involved; cholinergic, GABAergic, and glutamergic/aspartergic. The cholinergic system may play a role in generating or maintaining this type of seizure activity, and anticholinergics may protect against it provided they are given prior to commencement of behavioral seizures.(ABSTRACT TRUNCATED AT 400 WORDS)