Sutula T, Cavazos J, Golarai G
Neuroscience Training Program, University of Wisconsin, Madison 53792.
J Neurosci. 1992 Nov;12(11):4173-87. doi: 10.1523/JNEUROSCI.12-11-04173.1992.
Kainic acid, an analog of the excitatory amino acid L-glutamate, induces acute hyperexcitability and permanent structural alterations in the hippocampal formation of the adult rat. Administration of kainic acid is followed by acute seizures in hippocampal pathways, neuronal loss in CA3 and the hilus of the dentate gyrus, and reorganization of the synaptic connections of the mossy fiber pathway. Rats with these hippocampal structural alterations have increased susceptibility to kindling. To evaluate the role of the acute seizures and associated hippocampal structural alterations in the development of this long-lasting susceptibility, rats that received intraventricular kainic acid were cotreated with phenobarbital (60 mg/kg, s.c., once daily). Treatment with this dose for 5 d after administration of kainic acid suppressed acute seizure activity, protected against excitotoxic damage in the dentate gyrus, reduced mossy fiber sprouting, and completely abolished the increased susceptibility to kindling associated with kainic acid. Brief treatment with phenobarbital modified the pattern of damage and synaptic reorganization in the dentate gyrus in response to seizure-induced injury, and altered the long-lasting functional effects associated with hippocampal damage. As phenobarbital treatment did not protect against neuronal damage in CA3 or other regions of the hippocampus, the circuitry of the dentate gyrus was implicated as a locus of cellular alterations that influenced the development of kindling. These observations are evidence that pharmacological intervention can prevent the development of epilepsy in association with acquired structural lesions, and suggest that pharmacological modification of cellular responses to injury can favorably alter long-term functional effects of CNS damage.
kainic 酸是兴奋性氨基酸 L-谷氨酸的类似物，可诱导成年大鼠海马结构急性兴奋性过高和永久性结构改变。注射 kainic 酸后，海马通路会出现急性癫痫发作，CA3 区和齿状回门区的神经元会丢失，苔藓纤维通路的突触连接会重新组织。具有这些海马结构改变的大鼠对点燃的易感性增加。为了评估急性癫痫发作和相关海马结构改变在这种长期易感性发展中的作用，给接受脑室内注射 kainic 酸的大鼠联合使用苯巴比妥（60mg/kg，皮下注射，每日一次）。在注射 kainic 酸后用该剂量治疗 5 天，可抑制急性癫痫发作活动，防止齿状回发生兴奋性毒性损伤，减少苔藓纤维发芽，并完全消除与 kainic 酸相关的点燃易感性增加。苯巴比妥的短期治疗改变了齿状回对癫痫诱导损伤的损伤模式和突触重组，并改变了与海马损伤相关的长期功能效应。由于苯巴比妥治疗不能防止 CA3 区或海马其他区域的神经元损伤，因此齿状回的神经回路被认为是影响点燃发展的细胞改变部位。这些观察结果证明，药物干预可以预防与获得性结构损伤相关的癫痫发展，并表明对细胞损伤反应的药物修饰可以有利地改变中枢神经系统损伤的长期功能效应。
