Effects of vitamin B3 on traumatic brain injury

描述(申请人提供)：每年约有200万美国人遭受中到重度创伤性脑损伤(TBI)。这些损伤会产生持久的残疾，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令人震惊。最危险的人群之一是老年人，他们的死亡率是年轻患者的两倍。年龄的增长也被证明会导致更差的行为和病理结果。使这一重大公共卫生问题变得混乱的事实是，目前对遭受脑外伤的患者几乎没有药物治疗选择。此外，大多数临床前治疗药物从未在老年动物身上进行过测试，许多新合成的药物在临床测试的各个阶段都失败了。考虑到新合成药物在临床试验中失败的事实，似乎有理由开始检查更多天然物质的潜在疗效。最近的研究表明，皮质挫伤(CCI)后应用维生素B3(B3)可显著改善感觉运动和认知功能的恢复，并减轻损伤后发生的许多继发性病理生理变化(如神经变性、水肿性形成和反应性胶质增生)。这项拟议的研究将进一步利用慢性和严重脑外伤相关行为损害的动物模型来研究B3的临床前疗效。我们将使用中年(15月龄)大鼠在CCI模型中制造严重的缺陷，以测试B3‘S改善这些缺陷的能力。本研究的具体目的是：1)确定中年大鼠脑损伤后给予B3是否可以显著减少脑损伤后的感觉运动和认知障碍；2)确定中年大鼠脑损伤后给予B3是否可以减少脑损伤后的水肿；3)确定B3的治疗是否可以减少中年大鼠脑损伤后神经元的死亡、细胞凋亡和反应性胶质细胞增生；以及4)确定增龄是否对脑损伤后的脑水肿、神经变性、细胞凋亡和GFAP增殖具有有害影响。这里提出的研究将确定B3是否能够克服与中年受试者脑外伤相关的严重行为和病理后果。这将是确定B3作为脑损伤临床治疗方法的参数的关键一步。

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.