PARP Inhibitor for Improving Functional Recovery After TBI & Binge Alcohol Intoxication

这项研究的长期目标是为美国退伍军人提供更好的治疗选择 脑损伤(TBI)，在脑损伤之前滥用酒精。酒精滥用是退伍军人管理局的高度优先事项，因为 它在美国军队中的发病率很高，作为退伍军人一直延续到平民生活中。这是一个令人震惊的统计数据， 与患有酒精滥用障碍的退伍军人相关的是，每年有120万人在血液中酒精水平的情况下发生脑损伤 超过0.08%的法定驾驶限制。虽然令人衰弱的后果对许多幸存者构成了挑战，但 由于酒精滥用引起的神经炎症，在创伤性脑损伤前滥用酒精面临更糟糕的临床结果。 目前的治疗方法包括认知、物理、语言和职业治疗，伴有头痛或焦虑。 药物治疗，但没有有效的药物治疗来改善神经功能恢复， 尤其是在酗酒之后。 解决这一治疗差距，并提供更好的治疗选择，以改善长期的神经学 美国退伍军人的功能恢复，这项研究将调查重新定位肿瘤学的有效性 治疗，一种聚(ADP)核糖聚合酶(PARP)抑制剂，用于治疗因酒精滥用而加重的脑损伤。我们最近 结果表明，PARP抑制剂可以防止酗酒所致的神经炎性/退行性反应 曝光。因此，PARP抑制剂可能会促进因酒精滥用而加重的脑损伤患者的功能恢复。 这项提议的总体目标是测试在体内的可行性和有效性 改善神经功能恢复的药理学方法(口服PARP抑制剂) 在酗酒和脑外伤后。中心假设是，抑制PARP将减少TBI 酒精加重神经炎症，以促进功能恢复。这一中心假设将得到检验。 在大鼠中，通过以下特定目的：1)确定损伤后口服PARP抑制剂是否改善功能 通过测量海马区依赖的空间记忆恢复酒精中毒和脑损伤后的康复 功能，通过Morris水迷宫(MWM)任务。支持学习和记忆的大脑区域(海马体 和内嗅皮层)非常容易受到酗酒和脑外伤的影响。2)确定PARP是否 酒精中毒后的抑制剂治疗和脑损伤可改善这些神经细胞的炎症/变性 通过量化神经变性(荧光素B)和神经炎症来确定脑区和病变周围区域 记号笔。神经炎症标记物将包括星形胶质细胞增生症的纤维酸性蛋白(GFAP)和波形蛋白， 和离子钙结合适配分子1(IBA1)和分化分子簇11B(CD11b)用于 小胶质细胞激活。将比较接受PARP抑制剂的大鼠对脑外伤和酒精的反应， Veliparib(ABT-888)，治疗1周(神经炎症/变性)和6周(功能性治疗) 伤病后恢复)。 这项提议是创新的，它聚焦于一种新的药理学方法来改善神经学。 酗酒和无创伤性脑损伤后的功能恢复。检测神经炎性疾病 反应也将促进我们改善功能结果的努力，因为神经炎症与 功能恢复受损。鉴于PARP抑制剂最近已被FDA批准用于肿瘤学 适应症、改变PARP抑制剂的用途用于酗酒和脑损伤是一种很有希望的途径 增强易于翻译的功能恢复。这项工作有望对美国产生积极影响 患有因滥用酒精而加剧的脑损伤的退伍军人，还将生成 未来VA Merit和NIH为临床试验提供资金，最终改善他们的治疗选择。

The long-term goal of this research is to provide better therapeutic options for US veterans with traumatic brain injury (TBI) that misuse alcohol prior to TBI injury. Alcohol misuse is a high priority for the VA because of its high prevalence in the US military, which continues into civilian life as veterans. An alarming statistic, highly relevant to veterans with alcohol misuse disorder, is that 1.2 million TBIs occur annually with blood alcohol levels exceeding the 0.08% legal driving limit. While debilitating consequences challenge many survivors, patients that misused alcohol before TBI face worse clinical outcomes due to neuroinflammation arising from alcohol misuse. Current therapies include cognitive, physical, speech, and occupational therapy, with headache or anxiety medication, but no effective pharmacological treatment exists to improve functional neurological recovery, especially after alcohol misuse. To address this therapeutic gap and provide better therapeutic options to improve long-term neurological functional recovery for US veterans, this study will investigate the effectiveness of repurposing an oncology therapeutic, a poly(ADP)ribose polymerase (PARP) inhibitor, for TBI exacerbated by alcohol misuse. Our recent results indicate that PARP inhibitors can prevent neuroinflammatory/degenerative responses to binge alcohol exposure. Thus, PARP inhibitors may augment functional recovery in TBI exacerbated by alcohol misuse. The overall objective of this proposal is to test the in vivo feasibility and effectiveness of a novel pharmacological approach (an orally administered PARP inhibitor) in improving neurological functional recovery after binge alcohol intoxication and TBI. The central hypothesis is that PARP inhibition will diminish TBI neuroinflammation exacerbated by alcohol to improve functional recovery. This central hypothesis will be tested in rats by the following specific aims: 1) Determine if oral PARP inhibitor treatment after injury improves functional recovery after binge alcohol intoxication and TBI by measuring spatial memory, a hippocampus-dependent function, through Morris water maze (MWM) tasks. Brain regions supporting learning and memory (hippocampus and entorhinal cortex) are highly vulnerable to binge alcohol intoxication and to TBI. 2) Determine if PARP inhibitor treatment after binge alcohol intoxication and TBI improves the neuroinflammation/degeneration in these brain regions and the perilesional area by quantifying neurodegeneration (FluoroJade B) and neuroinflammation markers. Neuroinflammation markers will consist of fibrillary acid protein (GFAP) and vimentin for astrogliosis, and ionized calcium-binding adapter molecule 1 (Iba1) and cluster of differentiation molecule 11B (CD11b) for microglia activation. Responses to TBI and alcohol will be compared in rats receiving the PARP inhibitor, veliparib (ABT-888), to those without at 1 week (neuroinflammation/degeneration) and at six weeks (functional recovery) after injury. This proposal is innovative by focusing on a novel pharmacological approach to improve neurological functional recovery after binge alcohol intoxication and TBI where none exist. Testing neuroinflammatory responses will also advance our efforts to improve functional outcomes because neuroinflammation is linked to impaired functional recovery. Given that PARP inhibitors have been recently FDA-approved for oncology indications, repurposing PARP inhibitors for binge alcohol intoxication and TBI represent a promising avenue to augment functional recovery that is easily translatable. This work is expected have a positive impact on US veterans with TBI impairments exacerbated by alcohol misuse, and will also generate the pilot data needed for future VA Merit and NIH funding for clinical trials to ultimately improve their therapeutic options.