Aging as a risk factor for seizure-induced cell death

描述(申请人提供)：这项建议的重点是研究目标17。虽然申请人的实验室以前的研究证实，近交系小鼠对癫痫诱导的细胞死亡的易感性存在遗传差异，但目前的建议代表着研究人员进入了一个新的领域：衰老对癫痫和癫痫诱导的细胞死亡易感性的影响。了解衰老对大脑对化学损伤易感性的影响在老年医学和公共卫生中至关重要。虽然癫痫的发病和范围在健康的老年和患病的老年人群中都有所增加，但发病率增加的原因仍不清楚。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痫药物的能力而闻名。已知红藻氨酸会在海马体、杏仁核和相关的边缘通路产生实质性损害，并与包括癫痫在内的持久神经缺陷有关。因此，我们感兴趣的是，是否与年龄相关的对红藻氨酸的功能敏感性或耐受性的差异可能解释了与年龄相关的兴奋性毒素的明显超敏。这项拟议的研究将探索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。作为解决调节敏感性差异的药理学机制的第一步，我们将确定对兴奋性毒性细胞死亡的反应的差异性是否源于对红藻氨酸的药理敏感性的差异。我们提出了2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和癫痫诱导的细胞死亡的敏感性。在目标2中，我们将启动初步研究，以确定导致兴奋性毒性细胞死亡反应变异性的药理机制。具体地说，我们将表征对兴奋性毒性细胞死亡的反应的差异性是否源于品系或年龄相关的红藻氨酸输送到大脑的差异，第二，红藻氨酸注射的神经毒性效应是否可以通过给予谷氨酸拮抗剂来预防。这些实验的结果将有助于确定老化的大脑是否像年轻动物一样对神经毒性侮辱具有同样的敏感性，并将开始评估区分的机制基础。

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.