Evaluation of pH Dependent Neuroprotectants in SAH Model
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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.
