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

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Annual rept. 15 Sep 2010-14 Sep 2011

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Our major focus of year 1 of this grant were Aims 1 and 4. In Aim 1, we proposed to identify a maximally effective P2X7 receptor antagonist, as well as to optimize its dose in a weight drop model of experimental spinal cord injury. Solid progress has been made. The neuroprotective effect of the highest tolerated dose of four P2X7 receptor antagonists has been tested in rats and 3 P2X7 receptor antagonists have been tested in mice exposed to spinal cord injury. To identify actions of the potential new medication not related to P2X7 receptor inhibition, we obtaining permission from DOD to use mice instead of rats as our experimental model. Of 3 agents tested so far, only the P2X7 receptor antagonists BBG provided a significant neuroprotective effects in both rats and mice. The data collected shows 1 BBG effectively reduces the severity of spinal cord injury in rats, and 2 also protects in mice exposed to similar injury 3 P2X7 receptor KO mice exhibit significantly less injury than wild-type littermates 4 BBG has no neuroprotective effect in P2X7 receptor KO mice 5 combined these observations provide direct evidence suggesting that BBG educe the severity of SCI by antagonizing P2X7 receptors. The major goal of Aim 4, an additional focus of year 1, was to define the transcriptional events associated with spinal cord injury in spinal astrocytes and microglia, with a specific focus on those associated with and regulated by P2X7R activitydependent transcription.

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  • Medicine and Medical Research

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