Novel Neuroprotectants for TBI

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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.