Aging as a risk factor for seizure-induced cell death

描述（由申请人提供）：本提案的重点是研究目标17。虽然申请人实验室的先前研究已经确定，在近交系小鼠中对癫痫诱导的细胞死亡的易感性存在遗传差异，但本提议代表研究者进入了一个新的领域：衰老对癫痫发作和癫痫诱导的细胞死亡易感性的影响。关于衰老对大脑对化学损伤的易感性的影响的知识在老年医学和公共卫生中至关重要。虽然癫痫的发作和程度在健康老年人和患病老年人人群中均增加，但这种发病率增加的原因仍未探索。在用于研究神经毒性的不同实验模型中，红藻氨酸化学惊厥啮齿动物模型以其作为致癫痫剂的能力而闻名。已知红藻氨酸在海马体、杏仁核和相关边缘系统通路中产生实质性损伤，并且与包括癫痫发作在内的持久神经缺陷相关。因此，我们有兴趣确定是否年龄相关的差异，无论是功能敏感性红藻氨酸或耐受性可能占明显的年龄相关的超敏兴奋毒素。这项拟议中的研究将探讨老年小鼠比成年小鼠更容易受到红藻氨酸神经毒性的可能性。作为解决调节易感性差异的药理学机制的第一步，我们将确定兴奋性毒性细胞死亡反应的变异性是否来自对红藻氨酸的药理学敏感性差异。我们提出了两个目标来解决这些问题。在目标1中，我们将确定衰老是否可以调节对红藻氨酸诱导的癫痫发作和癫痫诱导的细胞死亡的敏感性。在目标2中，我们将启动试点研究，以确定药理学机制，有助于兴奋性毒性细胞死亡的反应的变化。具体来说，我们将表征是否变异性兴奋性细胞死亡的结果从应变或年龄依赖性差异红藻氨酸交付到大脑，其次，是否可以防止神经毒性作用的红藻氨酸管理的谷氨酸拮抗剂管理。这些实验的结果将有助于确定老化的大脑是否与年轻动物对神经毒性损伤具有相同的敏感性，并将开始评估差异的机制基础。

DESCRIPTION (provided by applicant): The focus of this proposal is Research Objective 17. While previous studies in the applicants' laboratory have established that there are genetic differences in susceptibility to seizure-induced cell death among inbred strains of mice, the present proposal represents entry into a new area for the investigator: The effects of aging on seizure and seizure-induced cell death susceptibility. Knowledge about the influence of aging on the susceptibility of the brain to chemical injury is of critical importance in geriatric medicine and public health. While the onset and extent of epilepsy increases in both healthy aged and diseased aged populations, the reasons for this increased incidence remain unexplored. Among the different experimental models used to study neurotoxicity, the kainic acid chemoconvulsant rodent model is well known for its ability to act as an epileptogenic agent. Kainic acid is known to produce substantial lesions in the hippocampus, the amygdala and related limbic pathways, and is associated with lasting neurological deficits including seizures. Thus, we are interested in determining whether age-related differences in either functional sensitivity to kainic acid or tolerance might account for the apparent age-related supersensitivity to excitotoxins. The proposed research will explore the possibility that aged mice are more susceptible to kainate neurotoxicity than their adult counterparts. As a first step to addressing the pharmacological mechanisms regulating susceptibility differences, we will determine whether variability in the response to excitotoxic cell death results from differences in the pharmacological sensitivity to kainate. We have proposed 2 Aims to address these issues. In Aim 1, we will determine whether aging can modulate sensitivity to kainate-induced seizures and seizure-induced cell death. In Aim 2, we will initiate pilot studies to determine the pharmacological mechanism that contributes to variability in the response to excitotoxic cell death. Specifically, we will characterize whether variability in the response to excitotoxic cell death results from strain-or age-dependent differences in kainate delivery to the brain, and secondly, whether the neurotoxic effects of kainate administration can be prevented by administration of glutamate antagonists. The results of these experiments will help determine if the aging brain has the same sensitivity to neurotoxic insults as that of younger animals, and will begin to evaluate the mechanistic basis for differential.