Novel Neuroprotectants for TBI

描述(由申请人提供)：目前还没有FDA批准的用于急性治疗创伤性脑损伤(TBI)的药物疗法来减轻破坏性的神经影响。然而，存在有效的药物干预的可能性，因为大多数创伤后变性是在组织初级机械损伤后几分钟、几小时甚至几天内发生的继发性事件的病理化学和病理生理学级联。这些继发性级联反应的早期因素包括兴奋性神经递质谷氨酸的过度释放、NMDAR的过度刺激、细胞内钙的大量增加、线粒体代谢障碍和蛋白水解酶Calain的激活。尽管大量证据表明，靶向谷氨酸受体介导的兴奋性毒性在各种神经损伤动物模型中具有神经保护作用；但还没有NMDAR拮抗剂显示出足够的有效性和安全性，可以在人类身上获得批准。NMDAR拮抗剂临床失败的常见原因包括不可接受的副作用，所需剂量低于最大疗效所需的剂量，以及在侮辱后给药时间太长。早期几代NMDAR拮抗剂(通道阻滞剂和谷氨酸或甘氨酸结合的竞争性阻滞剂)与显著的精神病和心血管副作用有关。作为非竞争性变构拮抗剂，NMDAR拮抗剂选择性地与含有NR2B亚单位的NMDA受体相互作用，比前一代NMDAR阻滞剂耐受性更好。CP101606是这类药物中的一种，在脑损伤患者的IIa期研究中取得了令人振奋的结果。最近，NeurOp，Inc.表明，正在开发的新一代NR2B特异性NMDAR阻滞剂具有独特的疾病激活机制，在动物缺血模型中提供有效的神经保护。作为同类药物的典范，NeurOp的93-31在正常pH下发挥最小的NMDAR拮抗作用，但在已知伴随缺血的pH降低时提供有效的NMDAR阻断。通过仅在需要时和在需要的地方阻断NMDAR，对pH敏感的NMDAR拮抗剂有望提供比上一代药物更好的治疗指数。在这个项目中，我们将探索与脑损伤伴随的pH下降是否足以激活NeurOp的93-31，以及该化合物是否在脑损伤的动物模型中提供神经保护。简介：美国每年约有150万人遭受创伤性脑损伤。数以千计的人经历了长期的脑损伤，这干扰了他们过上富有成效和充实生活的能力。我们计划测试一种很有前途的治疗创伤性脑损伤的新疗法。

DESCRIPTION (provided by applicant): There are no FDA approved pharmacological therapies for the acute treatment of traumatic brain injury (TBI) that mitigate damaging neurological effects. However, the potential for effective pharmacological intervention exists in that a majority of post-traumatic degeneration results from pathochemical and pathophysiological cascades of secondary events that occur in the minutes, hours and even days after the primary mechanical damage to tissue. Early factors in these secondary cascades include excessive release of the excitatory neurotransmitter glutamate, NMDAR over stimulation, a massive increase in intracellular calcium, mitochondrial metabolic failure and activation of the proteolytic enzyme calpain. Despite ample demonstration that targeting glutamate receptor-mediated excitotoxicity is neuroprotective in various animal models of neurological injury; no NMDAR antagonist has shown adequate efficacy and safety to be approved in man for TBI. Reasons frequently cited for the clinical failure of NMDAR antagonists include unacceptable side effects that required dosing regimes lower than needed for maximum efficacy and the administration of drug too long after the insult. Early generations of NMDAR antagonists (channel blockers, and competitive blockers of glutamate or glycine binding) were associated with significant psychotic and cardiovascular side effects. NMDAR antagonists that selectively interact with NMDA receptors containing the NR2B subunit as noncompetitive allosteric antagonists are better tolerated than prior generation NMDAR blockers. One in this class, CP101606, yielded promising results in a phase IIa study in TBI patients. Recently, NeurOp, Inc showed that a new generation of NR2B specific NMDAR blockers under development having a unique disease activated mechanism offer potent neuroprotection in animal models of ischemia. Exemplary of the class, NeurOp's 93-31 exerts minimal NMDAR antagonism at normal pH but offers potent NMDAR block at the reduced pH known to accompany ischemia. By blocking NMDAR only when and where needed, pH sensitive NMDAR antagonists are expected to offer a much improved therapeutic index over prior generation drugs. In this project we shall explore whether the pH drop that accompanies TBI is adequate to activate NeurOp's 93-31, and whether this compound provides neuroprotection in an animal model of TBI. Narrative: About 1.5 million people suffer traumatic brain injury in the US each year. Thousands experience long lasting brain injury that interferes with their ability to lead productive and full lives. We plan to test a promising new class of therapeutics for traumatic brain injury.