Gap Junctions and Hemichannels Composed of Connexins and Pannexins Mediate the Secondary Brain Injury Following Intracerebral Hemorrhage

SIMPLE SUMMARY: Intracerebral hemorrhage (ICH) is a leading medical problem without effective treatment options. The poor prognosis is attributed to the primary brain injury of the mechanical compression caused by hematoma, and secondary brain injury (SBI) that includes inflammation, glutamate excitotoxicity, oxidative stress and disruption of the blood brain barrier (BBB). Evidences suggests that gap junctions and hemichannels composed of connexins and pannexins regulate the inflammation and excitotoxicity insult in the pathological process of central nervous system disease, such as cerebral ischemia and neurodegeneration disease. In this manuscript, we discuss the fact that connexins- and pannexins-based channels could be involved in secondary brain injury of ICH, particularly through mediating inflammation, oxidative stress, BBB disruption and cell death. The details provided in this manuscript may help develop potential targets for therapeutic intervention of ICH. ABSTRACT: Intracerebral hemorrhage (ICH) is a devastating disease with high mortality and morbidity; the mortality rate ranges from 40% at 1 month to 54% at 1 year; only 12–39% achieve good outcomes and functional independence. ICH affects nearly 2 million patients worldwide annually. In ICH development, the blood leakage from ruptured vessels generates sequelae of secondary brain injury (SBI). This mechanism involves activated astrocytes and microglia, generation of reactive oxygen species (ROS), the release of reactive nitrogen species (RNS), and disrupted blood brain barrier (BBB). In addition, inflammatory cytokines and chemokines, heme compounds, and products of hematoma are accumulated in the extracellular spaces, thereby resulting in the death of brain cells. Recent evidence indicates that connexins regulate microglial activation and their phenotypic transformation. Moreover, communications between neurons and glia via gap junctions have crucial roles in neuroinflammation and cell death. A growing body of evidence suggests that, in addition to gap junctions, hemichannels (composed of connexins and pannexins) play a key role in ICH pathogenesis. However, the precise connection between connexin and pannexin channels and ICH remains to be resolved. This review discusses the pathological roles of gap junctions and hemichannels in SBI following ICH, with the intent of discovering effective therapeutic options of strategies to treat ICH.