EXCITOTOXIC MECHANISMS IN POST TRAUMATIC NEURONAL DEATH

创伤后神经元死亡的兴奋性毒性机制

• 批准号: 3415531
• 负责人: DOUGLAS T ROSS
• 金额: $ 13.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3415531
• 关键词: aminoacid; axon; brain injury; cell death; cerebral ischemia /hypoxia; dialysis therapy; disease /disorder model; electrophysiology; glutamate receptor; hippocampus; histochemistry /cytochemistry; immunocytochemistry; interneurons; intracranial pressure; iontophoresis therapy; laboratory rat; neural degeneration; neurotoxins; thalamic nuclei; trauma

The long range objectives of this research are to identify cellular mechanisms responsible for the death of selectively vulnerable neuronal populations following head injury in order to identify treatments which may prevent the development of debilitating neurological deficits. The role of excitatory amino acid toxicity (excitotoxicity) in degenerative processes which occur as a consequence of two components of concussive brain injury, mechanical cortical injury and partial ischemia due to raised intracranial pressure (ICP), will be examined separately and in combination using in vivo animal (rat) models. We will examined the hypothesis that aspects of head injury render selectively vulnerable populations of neurons hyperexcitable and that overexcitation mediated by excitatory amino acid receptors precipitates delayed neuronal degeneration. This study will directly examine the role of excitotoxicity in the degeneration of 3 vulnerable neuronal populations distant to sites of direct cortical injury, 1) specific thalamic relay nuclei which undergo retrograde degeneration following cortical injury, 2) hippocampal pyramidal neurons in the CA1 region of Ammon's horn which undergo delayed degeneration following ischemia due to elevated ICP, and 3) the GABAergic thalamic interneurons of the thalamic reticular nucleus (RT), which are even more sensitive to ischemia due to elevated ICP than the CA1 neurons. The use of the "isolated" ICP or mechanical injury models will allow a more controlled examination of the pathological processes initiated by these two components of concussive brain injury. Findings from these studies will facilitate the identification of compounds which might prevent neurodegeneration in the "combined" injury model which more closely resembles human concussive brain injury. The first specific aim is to determine concussive brain injury. This will be accomplished by characterizing the timecourse of alterations in ICP and depolarization consequent upon cortical impact in a model of concussive injury and comparing the patterns of neuronal loss using classical histological and immunohistochemical techniques seen in this model with those seen in models of cortical ablation or cisternal infusion to elevate ICP. The second specific aim is to investigate the role of excitotoxicity in the death of neurons in populations vulnerable to increased ICP or cortical lesions. This will be accomplished by performing intracranial microdialysis to establish whether the release of endogenous excitatory amino acids (EAAs) brings about excitotoxic conditions, and extracellular unit recording and microiontophoresis of EAA antagonists to determine which class(es) of EAA receptors mediate overexcitation following injury. The third aim is to determine whether prevention of excitotoxicity protects vulnerable neurons from degeneration following either elevated ICP, cortical lesions, or a combination of these insults such as occurs in the cortical impact model of concussive brain injury. Compounds found to prevent overexcitation of vulnerable neuronal populations will be administered to animals prior to or after the different types of injury and their efficacy in preventing neuronal loss will be examined using histological and immunohistochemical techniques 1 week to 3 months later. Because neuronal death in vulnerable populations is delayed from up to several days, antiexcitotoxic drugs can be effectively administered after the insult, offering a unique window for therapeutic intervention in pathological processes which would otherwise lead to the development of persisting neurological deficits. If memory deficits result from CA1 neuronal degeneration and attentional deficits occur as a consequence of RT degeneration following head injury then agents identified as being protective in our animal experiments would be potential candidates for clinical trials of head injury treatment.

这项研究的长期目标是识别细胞 选择性易损神经元死亡的机制 头部损伤后的人群，以确定可能的治疗方法 防止虚弱的神经缺陷的发展。的作用 退变过程中的兴奋性氨基酸毒性(兴奋性毒性) 这是脑震荡损伤的两个组成部分的结果， 颅内隆起致机械性皮质损伤和部分脑缺血 压力(ICP值)，将单独和结合使用 活体动物(大鼠)模型。我们将检验这一假设，即 头部损伤导致选择性易受伤害的神经元群体 兴奋性和兴奋性氨基酸介导的过度兴奋 受体加速延迟性神经元变性。这项研究将 直接检测兴奋性毒性在细胞退行性变中的作用 距离直接皮质损伤部位较远的脆弱神经元群体， 1)逆行变性的特定丘脑中继核团 皮质损伤后，2)海马CA1区锥体神经元 亚扪角区，延迟性退行性变 3)脑内GABA能丘脑间神经元的分布。 丘脑网状核(RT)，它对 脑缺血所致的ICP值高于CA1区神经元。的用法 隔离的颅内压或机械性损伤模型将允许更可控的 对这两种成分引发的病理过程的检查 脑震荡造成的脑损伤。这些研究的结果将有助于 抗神经退行性变化合物的鉴定 更接近人类脑震荡的“复合”损伤模型 脑部受伤。第一个明确的目标是确定脑震荡的大脑 受伤。这将通过表征时间进程来实现 大脑皮质撞击导致的颅内压和去极化的改变 脑震荡损伤模型的建立及神经元丢失模式的比较 使用经典的组织学和免疫组织化学技术 此模型与皮质消融或脑池模型中看到的模型相同 输液以升高颅内压。第二个具体目标是调查 兴奋性毒性在易感人群神经元死亡中的作用 颅内压升高或皮质损害。这将通过执行以下操作来实现 确定颅内微透析是否释放内源性 兴奋性氨基酸(EaAs)引起兴奋性毒性条件， EAA拮抗剂的细胞外单位记录和微离子导入 确定哪一类EAA受体在以下情况下介导过度兴奋 受伤。第三个目标是确定兴奋性毒性的预防 保护脆弱的神经元不受以下两种情况之一的影响 颅内压、皮质损害或这些侮辱的组合，如发生在 脑震荡脑损伤的皮质撞击模型。已发现的化合物 防止易受刺激的神经元种群过度兴奋 在不同类型的伤害之前或之后给动物注射 它们在防止神经元丢失方面的有效性将通过以下方法进行检验 术后1周~3个月行组织学和免疫组织化学检查。 因为脆弱人群中的神经元死亡从最高可推迟到 几天后，可以有效地使用抗兴奋性毒性药物 这一侮辱，为治疗干预提供了一个独特的窗口 病理过程，否则将导致发展 持续的神经缺陷。如果CA1导致记忆缺陷 RT导致神经元变性和注意障碍 头部损伤后的变性，然后被确认为 我们动物实验中的保护性将是潜在的候选者 颅脑损伤治疗的临床试验。