Penetrating brain injury and copper fragments in a rat model of posttraumatic Epilepsy

项目摘要 创伤性脑损伤(TBI)是平民和军人的主要神经问题，也是 最具破坏性的后果是创伤后癫痫(PTE)。几种类型的动物模型已经被 开发的目的是试图复制TBI和PTE的主要特征。许多研究小组都曾试图 使用这些啮齿动物模型来研究PTE，但我们和其他几个小组发现，只有 一小部分脑损伤的啮齿动物实际上会出现真正的自发性反复发作，这是 PTE的标志。事实上，许多关于PTE的回顾研究的临床报告，包括经典的 Anenerers和他的同事(1998)发现，在经历过的许多患者中，只有一小部分 TBI实际上会发展成PTE；然而，对这些人来说，它可能会严重削弱他们的身体素质。在中国的实验 这项研究计划旨在修改其中一种动物模型，受控皮质冲击(CCI)，在某种程度上 使其包括模拟具有小金属碎片的穿透TBI，就像在枪击中发生的那样 爆炸造成的伤口或导弹伤。我们的初步研究强烈表明，结合CCI- 铜碎片损伤使其从相对较少的癫痫发作次数转变为最多的 动物有自发性的反复发作，而且发生的频率相对较高。我们的建议 实验旨在验证这样一种假设，即带有铜碎片的TBI，就像现代枪击中发生的那样 头部创伤，极大地增强了脑外伤CCI模型的自发性反复发作。这些 研究不仅将为TBI的哪些特征提供关键的新见解，实际上是一些 毁灭性的PTE形式，但也将为未来修改动物模型提供框架 TBI使我们能够提供更好的自发性癫痫的对症治疗，并找到更好的 阻止创伤后癫痫发生的治疗方法。

Project Summary Traumatic brain injury (TBI) is a major neurological problem for both civilians and military personnel, and one of the most devastating outcomes is posttraumatic epilepsy (PTE). Several types of animal models have been developed to attempt to replicate the major features of TBI and PTE. Many research groups have attempted to use these animal models in rodents to study PTE, but we and several other groups have found that only a small fraction of brain-injured rodents actually develop genuine spontaneous recurrent seizures, which are the hallmark of PTE. Actually, many clinical reports of retrospective studies of PTE, including the classical work of Annegers and coworkers (1998), have found only a small fraction of the many patients who have experienced TBI actually develop PTE; however, for those individuals it can be profoundly debilitating. The experiments in this research proposal aim to modify one of these animal models, controlled cortical impact (CCI), in a manner to make it include a simulation of a penetrating TBI with small metal fragments, as would occur with a gunshot wound or a missile injury from an explosion. Our preliminary studies strongly suggest that combining a CCI- injury with copper fragments converts it from one with a relatively small number of seizures to one where most animals have spontaneous recurrent seizures and they occur at a relatively high frequency. Our proposed experiments aim to test the hypothesis that a TBI with copper fragments, as would occur in a modern gunshot wound to the head, greatly enhances the spontaneous recurrent seizures in the CCI model of TBI. These studies would not only provide critical new insights into what characteristics of the TBI actually underlie some devastating forms of PTE, but would also provide the framework for future modifications of animal models of TBI to allow us to provide better symptomatic treatment of the spontaneous seizures, and to find better therapies to block the development of posttraumatic epileptogenesis.