Effects of vitamin B3 on traumatic brain injury

描述（由申请人提供）：每年约有200万美国人遭受中度至重度创伤性脑损伤（TBI）。这些伤害会造成持久的残疾，包括认知、感觉、运动和情感障碍。与这些伤害相关的医疗费用是惊人的。最危险的人群之一是老年人，他们的死亡率可能是年轻患者的两倍。年龄的增长也被证明会导致更糟糕的行为和病理结果。混淆这一重大公共卫生问题的事实是，目前对患有TBI的患者的药物治疗选择很少。此外，大多数临床前治疗药物从未在老年动物中进行过测试，许多新合成的药物在临床测试的各个阶段都失败了。鉴于新合成的药物在临床试验中失败的事实，开始检查更天然物质的潜在功效似乎是合理的。最近已经证明，在皮质挫伤损伤（CCI）后给予维生素B3（B3）导致感觉运动和认知功能的恢复的显著改善，以及损伤后发生的许多继发性病理生理学变化（即，神经变性、水肿形成和反应性神经胶质增生）。拟议的研究将利用慢性和严重TBI相关行为障碍的动物模型进一步研究B3的临床前疗效。我们将在CCI模型中使用中年（15个月大）大鼠来产生严重的缺陷，以测试B3改善这些缺陷的能力。本研究的具体目的是：1）确定损伤后给予B3是否可以显著减少中年大鼠TBI后观察到的感觉运动和认知障碍; 2）确定中年大鼠损伤后给予B3是否可以减少TBI后损伤诱导的水肿; 3）确定损伤后给予B3是否可以减少中年大鼠损伤后的神经元死亡、凋亡和反应性胶质增生;和4）确定年龄增加是否对TBI后的脑水肿、神经变性、细胞凋亡和GFAP增殖具有有害影响。本文提出的研究将确定B3是否可以克服与中年受试者TBI相关的严重行为和病理结果。这将是确定开发B3作为TBI临床治疗的参数的关键步骤。

DESCRIPTION (provided by applicant): Annually, approximately 2 million Americans suffer a moderate to severe traumatic brain injury (TBI). These injuries produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries are staggering. One of the most at risk populations are the elderly, who can show twice the mortality of younger patients. Increasing age has also been shown to result in worse behavioral and pathological outcome. Confounding this major public health issue is the fact that currently there are very few pharmacological treatment options for patients who have suffered TBI. In addition, most preclinical therapeutics are never tested in older animals and many newly synthesized drugs fail in various stages of clinical testing. Given the fact that newly synthesized drugs fail in clinical trials it seems reasonable to begin to examine the potential efficacy of more natural substances. It has recently been demonstrated that administration of vitamin B3 (B3) following cortical contusion injury (CCI) resulted in a significant improvement in recovery of sensorimotor and cognitive function, as well as in a reduction of many of the secondary pathophysiological changes that occur following injury (i.e., neurodegeneration, edema formation and reactive gliosis). The proposed research will further investigate the preclinical efficacy of B3 utilizing an animal model of chronic and severe TBI-related behavioral impairments. We will use middle-aged (15 month old) rats in the CCI model to produce the severe deficits in order to test B3's ability to improve these deficits. The specific aims of this study are to: 1) determine if administration of B3 following injury can significantly reduce the sensorimotor and cognitive impairments seen following TBI in middle- aged rats; 2) determine if administration of B3 following injury in middle-aged rats can reduce injury-induced edema following TBI; 3) determine if administration of B3 following injury can reduce neuronal death, apoptosis and reactive gliosis following injury in middle-aged rats; and 4) determine if increased age has a deleterious effect on cerebral edema, neurodegeneration, apoptosis, and GFAP proliferation following TBI. The research proposed here will determine if B3 can overcome the severe behavioral and pathological outcomes associated with TBI in middle-aged subjects. This will be a critical step in determining the parameters for the development of B3 as a clinical treatment for TBI.