Development of a small molecule P 2 X 7 R antagonist

Spinal cord injury (SCI) is often complicated by secondary ischemic injury as a result of the innate inflammatory response to traumatic injury and tissue swelling. Prior studies have shown that excessive ATP release from peri-traumatic regions contributes to the inflammatory response to SCI by activation of low affinity P2X7 receptors. Since connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact of deletion of connexins (Cx30/Cx43) in astrocytes on post-traumatic ATP release. In vivo bioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates. Moreover, astrogliosis and microglia activation were reduced in peri-traumatic areas of mice lacking Cx43. Motor recovery was also significantly improved and the traumatic lesion smaller in mice with deletion of Cx43. Combined, these observations demonstrate that astrocytic hemichannels contributes to post-traumatic ATP release, which in turn aggravates secondary injury and restrains functional recovery following experimental spinal cord injury. Cx43 hemichannels may thereby constitute a new therapeutic target in spinal cord injury.