Evaluation of pH Dependent Neuroprotectants in SAH Model

描述（由申请人提供）：本STTR项目的目的是确定NeurOp的pH敏感性NMDAR拮抗剂是否可改善经验证的蛛网膜下腔出血（SAH）后血管痉挛小鼠模型的功能恢复并减少神经元损伤。蛛网膜下腔出血（SAH）占所有卒中的10%;然而，与其他类型的卒中不同，SAH的发病率并未下降。尽管在早期诊断和管理方面取得了进展，但SAH仍然是死亡和残疾的常见原因。许多动物研究已经证实NMDA受体作为中风、脑和脊髓损伤以及涉及缺血的相关环境中的神经保护的靶点。不幸的是，前三代NMDAR拮抗剂（通道阻断剂和谷氨酸或甘氨酸结合的竞争性阻断剂）由于毒副作用（例如精神病症状和心血管作用）而未被证明在临床上有用。此外，由于需要在缺血性损伤后及时（约3小时内）施用药物，在缺血性环境如急性中风中实现有效的神经保护已被证明是具有挑战性的（Saver et.例如，2004年）。在20世纪80年代后期，发现了一类新的NMDAR拮抗剂（苯乙醇胺），其在激动剂结合位点处不结合（Gotti等人，1988年）。苯乙醇胺类如艾芬地尔在短暂性缺血的临床前啮齿动物模型中显示出神经保护特性（厄利et al.，1996; Dogan等人，1997年）。值得注意的是，这类拮抗剂缺乏其他类型NMDAR拮抗剂的严重副作用倾向（博伊斯等人，1999;肯普和麦克南，2002）。在帮助阐明苯乙醇胺的作用机制的工作中，NeurOp创始人发现质子调节NMDAR（Traynelis & Cull-Candy，1991; Traynelis等人，1995年）。他们进一步表明，苯乙醇胺增强或增强受体对质子的敏感性，从而下调受体功能（Mott等人，1998年）。这些发现启发NeurOp的创始人设计了新一代pH敏感型NMDAR拮抗剂。受体固有的pH敏感性吸引人将其用作激活机制，因为众所周知，局部酸化或pH下降伴随缺血（Katerina www.example.com 1992）和其他病理状况（神经性疼痛、运动障碍）。一种神经保护剂，其为：a）在局部缺血发作过程中加入和; B）限制作用于局部缺血区域，将有望克服两个问题，这两个问题破坏了现有NMDAR拮抗剂治疗局部缺血的临床成功，治疗窗短和副作用。SAH提出了一个令人信服的迹象，其中测试NeurOp的神经保护剂，因为在这种情况下，它是可行的，开始神经保护治疗在一个良好的控制设置，天前的延迟缺血性损伤的许多SAH患者遭受。公共卫生相关性：缺血性损伤导致的人类痛苦和经济成本是巨大的。在美国，中风的估计总成本为每年568亿美元（美国心脏协会，心脏病和中风统计-2005年更新）。蛛网膜下腔出血（SAH）占所有卒中的10%;然而，与其他类型的卒中不同，SAH的发病率并未下降。尽管在早期诊断和管理方面取得了进展，但SAH仍然是死亡和残疾的常见原因。在这个项目中，有希望的新药可能有一天会保护脑组织免受SAH和中风造成的损害，将在缺血的动物模型中进行测试。

DESCRIPTION (provided by applicant): The goal of this STTR project is to determine if NeurOp's pH-sensitive NMDAR antagonists improve functional recovery and reduce neuronal injury in a validated murine model of vasospasm following subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage (SAH) accounts for 10% of all strokes; however, unlike other types of stroke, the incidence of SAH is not declining. Despite advances in early diagnosis and management, SAH remains a frequent cause of death and disability. Numerous animal studies have validated NMDA receptors as targets for neuroprotection in stroke, brain and spinal cord injury and related settings that involve ischemia. Unfortunately, the first three generations of NMDAR antagonists (channel blockers, and competitive blockers of glutamate or glycine binding) have not proved useful clinically due to toxic side effects, such as psychotic symptoms and cardiovascular effects. In addition, achieving effective neuroprotection in ischemic settings such as acute stroke has proven challenging due to the need for timely (within ~3 hours) administration of drug following the ischemic insult (Saver et. al., 2004). In the late 1980's a new class of NMDAR antagonist (phenylethanolamines) was discovered that does not bind at the agonist binding sites (Gotti et al., 1988). Phenylethanolamines like ifenprodil show neuroprotective properties in preclinical rodent models of transient ischemia (Earley et al., 1996; Dogan et al., 1997). Significantly, this class of antagonist lacks the severe side-effect liability of other types of NMDAR antagonist (Boyce et al., 1999; Kemp and McKernan, 2002). In work that helped elucidate the mechanism of action of phenylethanolamines, NeurOp founders discovered that protons modulate NMDAR (Traynelis & Cull-Candy, 1991; Traynelis et al., 1995). They further showed that phenylethanolamines enhance or potentiate receptor sensitivity to protons and thereby tune receptor function down (Mott et al., 1998). These findings inspired NeurOp's founders to design a new generation of pH sensitive NMDAR antagonists. The inherent pH sensitivity of the receptor was appealing to exploit as an activation mechanism because it is well known that focal acidification, or pH drop, accompanies ischemia (Katsura et.al 1992) and other pathological conditions (neuropathic pain, dyskinesia). A neuroprotectant that is: a) on-board during an ischemic attack and; b) restricted in action to the zone of ischemia, would be expected to overcome the two problems that undermined clinical success of prior NMDAR antagonist to treat ischemia short therapeutic window and adverse effects. SAH presents a compelling indication in which to test NeurOp's neuroprotectants because in this context it is feasible to commence neuroprotective therapy in a well controlled setting, days in advance of the delayed ischemic injury suffered by many SAH patients. PUBLIC HEALTH RELEVANCE: The human suffering and economic costs resulting from ischemic injury is enormous. The estimated total cost of stroke in the United States is $56.8 billion per year (American Heart Association, Heart Disease and Stroke Statistics-2005 Update). Subarachnoid hemorrhage (SAH) accounts for 10% of all strokes; however, unlike other types of stroke, the incidence of SAH is not declining. Despite advances in early diagnosis and management, SAH remains a frequent cause of death and disability. In this project promising new drugs that may one day protect brain tissue from damage caused by SAH and stroke will be tested in an animal model of ischemia.