Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia.
Keywords: ATP; connexin; gap junction; hemichannel; inflammasome; inflammation; ischemia; pannexin.