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。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。在一定程度上，这是因为许多新合成的药物在不同阶段的疗效测试中失败。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。最近已经证明，在实验诱导的中风后给予维生素B3(B3)可以减少大鼠脑梗塞的范围，并可以改善大鼠的行为结果。此外，镁药物疗法的临床前疗效已经得到了很好的证实。这项拟议的研究将调查B3在减轻脑损伤的生理后果和改善行为结果方面的潜在临床前疗效。我们将使用啮齿动物双侧额叶皮质挫伤模型，这类似于车祸中遭受的额头损伤。本研究的具体目的是：1)确定脑损伤后给予B3是否可显著减轻脑损伤后的认知和感觉运动障碍；2)确定脑损伤后B3药物治疗的最佳注射参数(即机会窗和剂量反应)；3)确定脑损伤后应用B3是否能显著减少脑损伤后细胞的水肿和镁的耗竭；4)确定B3药物治疗对脑损伤后细胞凋亡和反应性胶质细胞增生的影响。这里提出的研究将确定B3是否具有治疗脑损伤的临床前疗效，并开始确定B3作为临床治疗脑损伤的开发参数。

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. 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 part, this occurs because many newly synthesized drugs fail in various stages of efficacy 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 experimentally induced stroke reduces the size of the infarct and can improve behavioral outcome in rats. In addition, the preclinical efficacy of magnesium pharmacotherapy has been well established. The proposed research will investigate the potential preclinical efficacy of B3 to lessen the physiological consequences of brain injury and improve behavioral outcome. We will use the rodent bilateral frontal cortical contusion injury model, which is similar to a frontal head injury sustained in a car accident. The specific aims of this study are to: 1) determine if administration of B3 following injury can significantly reduce the cognitive and sensorimotor impairments seen following TBI; 2) determine the best injections parameters (i.e., window of opportunity and dose response) for B3 pharmacotherapy following TBI; 3) determine if administration of B3 following injury can significantly decrease the amount of injury-induced edema and injury-induced magnesium depletion; 4) determine the effect of B3 pharmacotherapy on apoptosis and reactive gliosis following TBI. The research proposed here will determine if B3 holds any preclinical efficacy for the treatment of TBI and begin to define the parameters for the development of B3 as a clinical treatment for TBI.