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Evaluation of pH Dependent Neuroprotectants in SAH Model

pH 依赖性神经保护剂在 SAH 模型中的评价

基本信息

批准号：
7483998
负责人：
DANIEL T LASKOWITZ
金额：
$ 14.41万
依托单位：
NEUROP, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483998
关键词：
Accounting Adverse effects Agonist American Heart Association Animal Model Animals Beds Behavioral Binding Binding Sites Brain Calcium Channel Candy Cardiovascular system Caring Cause of Death Cerebral Ischemia Cessation of life Class Clinic Clinical Condition Data Depth Dihydropyridines Drops Dyskinetic syndrome Early Diagnosis Economics End Point Evaluation Generations Glutamates Glycine Goals Heart Diseases Hour Human Incidence Injury Institution Ischemia Measures Modeling Mus N-Methyl-D-Aspartate Receptors Nervous System Trauma Neuronal Injury Neurons Neuroprotective Agents Nimodipine Patients Performance Personal Satisfaction Pharmaceutical Preparations Phase Property Protons Public Health Recovery of Function Rodent Model Small Business Funding Mechanisms Small Business Innovation Research Grant Small Business Technology Transfer Research Spinal cord injury Standards of Weights and Measures Stroke Subarachnoid Hemorrhage Symptoms Testing Therapeutic United States Update Upper arm Vasospasm Work acute stroke base brain tissue channel blockers cost day design dihydropyridine disability functional improvement functional outcomes ifenprodil improved member neuroprotection painful neuropathy pre-clinical programs receptor function receptor sensitivity statistics success

项目摘要

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.

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拮抗剂是否能改善蛛网膜下腔出血（SAH）后血管痉挛小鼠模型的功能恢复和减少神经元损伤。蛛网膜下腔出血（SAH）占所有中风的10%；然而，与其他类型的中风不同，SAH的发病率并没有下降。尽管在早期诊断和管理方面取得了进展，但SAH仍然是导致死亡和残疾的常见原因。大量的动物研究已经证实NMDA受体是中风、脑和脊髓损伤以及涉及缺血的相关情况下的神经保护靶点。不幸的是，前三代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）由于毒副作用（如精神病症状和心血管作用）在临床上没有被证明有用。此外，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具有挑战性，因为在缺血性损伤后需要及时（约3小时内）给药（Saver等，2004年）。在20世纪80年代末，一类新的NMDAR拮抗剂（苯乙醇胺）被发现不结合在激动剂结合位点（Gotti et al., 1988）。苯基乙醇胺如伊芬普罗地尔在临床前啮齿类动物短暂性缺血模型中显示出神经保护特性（Earley等，1996；Dogan等，1997）。值得注意的是，这类拮抗剂不像其他类型的NMDAR拮抗剂那样具有严重的副作用（Boyce et al., 1999; Kemp and McKernan, 2002）。在阐明苯乙醇胺作用机制的工作中，NeurOp的创始人发现质子可以调节NMDAR （Traynelis & Cull-Candy, 1991; Traynelis et al., 1995）。他们进一步表明，苯乙醇胺增强或增强了受体对质子的敏感性，从而降低了受体的功能（Mott et al., 1998）。这些发现启发了NeurOp的创始人设计新一代pH敏感的NMDAR拮抗剂。该受体固有的pH敏感性被认为是一种激活机制，因为众所周知，局灶性酸化或pH值下降伴随着缺血（Katsura et al . 1992）和其他病理状况（神经性疼痛、运动障碍）。一种神经保护剂，它是：A)在缺血性发作时在船上；b)作用局限于缺血区域，有望克服以往NMDAR拮抗剂治疗缺血临床成功的两个问题，即治疗窗口短和不良反应。SAH提供了一个令人信服的适应症来测试NeurOp的神经保护剂，因为在这种情况下，在控制良好的环境中开始神经保护治疗是可行的，在许多SAH患者遭受延迟性缺血性损伤的几天前。公共卫生相关性：缺血性损伤造成的人类痛苦和经济代价是巨大的。在美国，估计每年中风的总费用为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）占所有中风的10%；然而，与其他类型的中风不同，SAH的发病率并没有下降。尽管在早期诊断和管理方面取得了进展，但SAH仍然是导致死亡和残疾的常见原因。在这个项目中，有望有一天保护脑组织免受SAH和中风损伤的新药将在缺血动物模型中进行测试。