Development of a Small Molecule P2X7R Antagonist as a Treatment for Acute SCI.

摘要

This project is based on the premise that secondary damage following traumatic spinal cord can be limited by acute administration of P2X7 receptor antagonists. The objectives of the proposal were to screen P2X7 receptor antagonists in a weight drop model of spinal cord injury, define the clinical indications for administering the P2X7 receptor antagonist in various models of SCI, and obtain data for safety and toxicity data to support an IND application necessary to conduct a clinical trial. We have thus far made good progress and have validated that two P2X7 receptor antagonists, BBG and A-740003 have neuroprotective benefits in the setting of spinal cord injury in two species: rats and mice. Two other receptor antagonists (KN-62 and MRS2159) did not provide clinical benefits. An interesting discovery is that BBG possess neuroprotective effects that in part, are mediated by suppressing the endogenous inflammatory response to tissue injury, by P2X7 receptor independent pathways. This observation was based on the analysis of P2X7 receptor knockout mice. We believe that this observation is potentially of great importance because of BBG: The prospect of administering a small drug with no known adverse effects is particularly attractive in the setting of acute traumatic injury because transportation of patients with SCI is a specific concern.