PPAR-gamma as a therapeutic target after TBI

描述（由申请人提供）：每年，成千上万的人遭受创伤性脑损伤（TBI），大多数幸存者表现出中度至重度神经功能障碍。目前还没有已知的治疗方法可以预防人类脑外伤后继发性神经元死亡和/或促进神经系统恢复。脑损伤后几分钟内开始并持续数天的炎症被认为会促进继发性神经元死亡，从而导致运动功能障碍。由于在转录水平上控制炎症是预防神经元损伤的有效策略，本研究的目的是评估转录因子PPAR3激动剂罗格列酮在预防成年小鼠TBI后神经元死亡和神经功能障碍中的功效。先前的研究表明，他汀类药物的急性治疗也能诱导脑外伤后的神经保护作用，这与他汀类药物降低胆固醇的能力无关。他汀类药物增加PPAR表达，这被认为介导了他汀类药物在损伤后的一些多效有益作用。因此，我们希望测试是否可以通过与辛伐他汀共同治疗动物来增强罗格列酮治疗TBI后的治疗潜力和获益窗口。由于这两种化合物都是fda批准的，如果证明是有益的，这种组合可以迅速转化为临床应用，以尽量减少人类创伤性脑损伤后的神经功能缺陷。

DESCRIPTION (provided by applicant): Every year, thousands of humans suffer traumatic brain injury (TBI) and most of the survivors manifest moderate to severe neurological dysfunction. Currently no known therapies that can prevent secondary neuronal death and/or promote neurological recovery after TBI in humans are available. Inflammation that starts within minutes and sustains for days after brain injury is thought to promote the secondary neuronal death and thus motor dysfunction. As controlling inflammation at the level of transcription is an effective strategy to prevent the neuronal damage, the goal of this proposal is to evaluate the efficacy of the transcription factor PPAR3 agonist rosiglitazone in preventing neuronal death and neurological dysfunction following TBI in adult mice. Previous studies showed that acute treatment with statins also induce neuroprotection following TBI, which is independent of their capability to lower cholesterol. Statins increase PPAR expression which is thought to mediate some of the pleiotropic beneficial effects of statins after an injury. Hence, we wish to test if the therapeutic potential and the window of benefit of rosiglitazone treatment following TBI can be enhanced by co-treating the animals with simvastatin. As both these compounds are FDA-approved, if proven beneficial, the combination can be quickly translated into clinical use to minimize the neurological deficits following TBI in humans. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a leading cause of disability in the world with few current therapeutic options. This proposal wishes to evaluate if a combination therapy with rosiglitazone and simvastatin (two FDA-approved drugs) can prevent the secondary neuronal death and thus neurological dysfunction after traumatic brain injury in mice. The ultimate goal is to identify drugs that benefit the recovery of brain trauma patients.