Chronic TBI Bcl 2-20:34 Protection Against Lowered Seizure Susceptibility

描述(由申请人提供)： 颅脑损伤是一种常见的战斗性损伤。不幸的是，头部创伤的幸存者可能会在以后出现反复发作的症状。这一问题被称为创伤后癫痫，与严重的发病率和死亡率有关。最常见的创伤后癫痫起源于颞叶的海马体。多达三分之一的这类患者患有难治性创伤后癫痫。因此，他们面临着一些并发症的风险，包括猝死、身体损伤、记忆力丧失和一系列心理社会问题。由于这个问题，美国癫痫学会呼吁对创伤后癫痫进行长期研究。因此，我们量身定做了我们的建议，以提供满足这一需求的信息。在我们的初步研究中，我们在成年雄性大鼠上使用了一种名为受控皮质冲击(CCI)的脑创伤模型，发现CCI后癫痫阈值不仅降低，而且在此后至少6个月内持续下降。此时，我们建议在成年大鼠约24个月的生命周期内，对侧方CCI后的癫痫阈值进行慢性评估。在此期间，我们计划在体外和体内进行电生理、组织学和生化实验，以评估CCI后每6个月一次的海马亚区，包括齿状回、CA3和CA1的惊厥阈值。在我们的初步研究中，我们还发现，有证据表明，用Bcl-220-34多肽治疗可以防止CCI后癫痫阈值的降低。因此，我们也将在我们的提案中评估这一治疗策略。此外，我们还将研究Bcl-220-34多肽的潜在作用机制，这可能表明线粒体参与了脑损伤后癫痫阈值降低的产生。为此，我们还将评估CCI后使用和不使用Bcl220-34肽治疗后线粒体的结构和功能。

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) is a frequent combat injury. Unfortunately, survivors of head trauma may go on later to develop recurrent seizures. This problem, termed post-traumatic epilepsy, is associated with significant morbidity and mortality. The most common form of post-traumatic epilepsy originates in the hippocampus of the temporal lobe. Up to one third of such patients have medically intractable post- traumatic epilepsy. As such they are at risk for a number of complications including sudden death, physical injuries, memory loss and a host of psychosocial issues. Due to this problem, a call has been made by the American Epilepsy Society for chronic studies of post-traumatic epilepsy. Therefore, we have tailored our proposal to provide information for this need. In our preliminary studies, we have used a model of TBI called controlled cortical impact (CCI) in adult male rats and found that seizure threshold is not only decreased after CCI, but continues to decline for at least 6 months thereafter. At this time we propose to evaluate seizure threshold chronically after lateral CCI over the life-span of the adult rat, which is about 24 months. During that time, we plan to perform electrophysiological, histological and biochemical experiments in vitro and in vivo techniques to evaluate seizure threshold in hippocampal subregions, including the dentate, CA3 and CA1 every 6 months after CCI. We have also found in our preliminary studies, evidence that treatment with the Bcl-220-34 peptide may prevent the lowering of seizure threshold after CCI. Therefore, we will also evaluate this treatment strategy in our proposal. In addition, we will examine a potential mechanism of action for the Bcl-220-34 peptide, which may indicate mitochondrial involvement in the generation of lowered seizure threshold after TBI. To this end, we will also evaluate mitochondrial structure and function after CCI with and without treatment with the Bcl-220-34 peptide.