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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）：本提案的重点是研究目标17。虽然申请人实验室先前的研究已经确定，在近交系小鼠中，对癫痫诱发的细胞死亡的易感性存在遗传差异，但目前的提议代表着研究者进入了一个新的领域：衰老对癫痫和癫痫诱发的细胞死亡易感性的影响。了解衰老对大脑化学损伤易感性的影响在老年医学和公共卫生领域至关重要。虽然健康老年人和患病老年人群中癫痫的发病和程度都在增加，但发病率增加的原因仍未查明。在用于研究神经毒性的不同实验模型中，kainic酸化学惊厥啮齿动物模型以其作为致痫剂的能力而闻名。已知Kainic酸会在海马体、杏仁核和相关边缘通路中产生实质性损伤，并与包括癫痫发作在内的持久神经功能障碍有关。因此，我们感兴趣的是确定年龄相关的对kainic酸的功能敏感性或耐受性的差异是否可以解释明显的年龄相关的对兴奋毒素的超敏感性。拟议的研究将探索老年小鼠比成年小鼠更容易受到海因酸盐神经毒性的可能性。作为解决调节易感性差异的药理学机制的第一步，我们将确定对兴奋毒性细胞死亡反应的变异性是否源于对盐酸盐药理学敏感性的差异。我们提出了两个目标来解决这些问题。在Aim 1中，我们将确定衰老是否可以调节对盐酸盐诱导的癫痫和癫痫诱导的细胞死亡的敏感性。在目标2中，我们将启动试点研究，以确定导致兴奋性毒性细胞死亡反应变异性的药理学机制。具体来说，我们将描述对兴奋毒性细胞死亡反应的可变性是否源于菌株或年龄依赖的海碱盐向大脑递送的差异，其次，是否可以通过谷氨酸拮抗剂来预防海碱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，并将开始评估这种差异的机制基础。