Aging as a risk factor for seizure-induced cell death

衰老是癫痫引起的细胞死亡的危险因素

基本信息

批准号：
7227860
负责人：
PAULA E SCHAUWECKER
金额：
$ 6.96万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227860
关键词：
AMPA Receptors Accounting Address Adult Affect Age Age-Months Aging Amygdaloid structure Animals Area Behavioral Blood - brain barrier anatomy Brain CBA/J Mouse Cell Death Chemical Injury Child Development Diagnosis Disease Dose Drug Kinetics Elderly Epilepsy Event Excitatory Amino Acid Antagonists Excitatory Neurotoxins Experimental Models Genetic Geriatrics Hippocampus (Brain)Human Inbred Strains Mice Incidence Injection of therapeutic agent Injury Kainic Acid Knowledge Laboratories Lesion Life Mediating Modeling Mus N-Methylaspartate Neurologic Outcome Pathway interactions Personal Satisfaction Persons Pilot Projects Pongidae Population Predisposition Propionic Acids Propionic acid Public Health Quinoxalines Rate Recurrence Research Research Personnel Risk Risk Factors Rodent Model Sclerosis Seizures Stroke Synapses Temporal Lobe Epilepsy Time age effect age related aged aging brain base healthy aging interest juvenile animal kainate male middle age nervous system disorder neuropathology neurotoxic neurotoxicity prevent receptor research study response young adult

项目摘要

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.

描述（由申请人提供）：该提案的重点是研究目标17。尽管申请人实验室的先前研究已经确定，在小鼠的近交菌株中，对癫痫发作诱导的细胞死亡的易感性存在遗传差异，但目前的提案代表了研究器的新领域，进入了研究器的新区域：对衰老和癫痫病的影响对癫痫发作和癫痫病的影响。关于衰老对大脑对化学损伤敏感的影响的知识在老年医学和公共卫生中至关重要。尽管健康老年和患病的人群的癫痫发作和程度都在增加，但发病率增加的原因仍未开发。在用于研究神经毒性的不同实验模型中，海藻酸化学弹跳啮齿动物模型以其充当癫痫剂的能力而闻名。已知海藻酸会在海马，杏仁核和相关边缘途径中产生大量病变，并与包括癫痫发作在内的持久神经系统缺陷有关。因此，我们有兴趣确定对Kainic Acid的功能敏感性或耐受性的年龄相关差异是否可能解释与年龄相关的兴奋毒素的明显超敏反应。拟议的研究将探讨年龄小鼠比成人对应物更容易受到海藻酸盐神经毒性的可能性。作为解决调节易感性差异的药理机制的第一步，我们将确定对兴奋性细胞死亡的反应的变异性是否是由于药理学对海谷酸盐敏感的差异而导致的。我们提出了2个目的，目的是解决这些问题。在AIM 1中，我们将确定衰老是否可以调节对海藻酸盐诱导的癫痫发作和癫痫发作诱导的细胞死亡的敏感性。在AIM 2中，我们将启动试点研究，以确定导致兴奋性细胞死亡反应可变性的药理机制。具体而言，我们将表征对兴奋性细胞死亡的反应的变异性是否是由于菌株或年龄依赖性的海藻酸盐递送向大脑的差异而导致的，其次，是否可以通过给药谷氨酸拮抗剂来预防海关酸盐给药的神经毒性作用。这些实验的结果将有助于确定衰老的大脑对神经毒性损伤的敏感性是否与幼小动物相同，并将开始评估差异的机械基础。