Effects of vitamin B3 on traumatic brain injury

描述（由申请人提供）：每年，大约有200万美国人遭受中度至重度创伤性脑损伤（TBI）。这些损伤会产生永久性残疾，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。混淆这一重大公共卫生问题的事实是，目前对创伤性脑损伤患者的药物治疗选择非常少。部分原因是，许多新合成的药物在功效测试的各个阶段都失败了。鉴于新合成药物在临床试验中失败的事实，开始研究更多天然物质的潜在功效似乎是合理的。最近有研究表明，在实验性脑卒中后给予维生素B3 （B3）可减少梗死面积，并可改善大鼠的行为结果。此外，镁药物治疗的临床前疗效已经得到了很好的证实。本研究将探讨B3在减轻脑损伤生理后果和改善行为结果方面的潜在临床前疗效。我们将使用啮齿类动物双侧额叶皮质挫伤模型，该模型类似于车祸中遭受的额叶头部损伤。本研究的具体目的是：1)确定脑外伤后服用B3是否能显著减少脑外伤后的认知和感觉运动障碍；2)确定TBI后B3药物治疗的最佳注射参数（即机会窗和剂量反应）；3)确定损伤后给药B3是否能显著降低损伤性水肿量和损伤性镁耗竭；4)确定B3药物治疗对脑外伤后细胞凋亡和反应性胶质瘤的影响。这里提出的研究将确定B3是否具有治疗TBI的临床前疗效，并开始确定B3作为TBI临床治疗的发展参数。

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.