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

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.

Dysfunctional cGMP Signaling Leads to Age-Related Retinal Vascular Alterations and Astrocyte Remodeling in Mice

“…It is possible that by disrupting the cGMP signaling pathway, the process of gap junction turnover and renewal is affected, leading to more greatly reduced levels in the GC1 −/− mice compared to Wt with age. Furthermore, Cx43 mediates the redistribution of metabolic resources in response to retinal injury [ 46 ] and has a role in the spread of pro-survival and pro-apoptotic molecules in response to injury [ 47 ]. Reductions in Cx43 through blockade have been associated with neuroprotective responses [ 48 ], and therefore reduced connexin expression could be useful in slowing the spread of degenerative factors.…”

Oxidative Stress Following Intracerebral Hemorrhage: From Molecular Mechanisms to Therapeutic Targets

“…After ICH, excessive glutamate exacerbates injury by stimulating NMDA receptors ( 49 ). Correspondingly, oxidation products were shown to enhance glutamate release through increasing connexins and pannexins based channel activity following ICH ( 10 ). ROS/RNS regulate the change of connexin and pannexin-based channel properties both in systemic vasculature and brain cells ( 66 ).…”

“…The poor prognosis is attributed to the primary brain injury caused by the hematoma (4), and secondary brain injury attributed to neuroinflammation, excitatory amino acid, oxidative stress (OS), cytotoxicity of blood, hypermetabolism and spreading depression (5)(6)(7). In addition to limited progress in the management of ICH patients, effective treatment options are yet to be developed for the secondary brain injury of ICH (8)(9)(10)(11)(12).…”

Modes of Brain Cell Death Following Intracerebral Hemorrhage

“…However, the number of deaths (2.8 million) globally due to hemorrhagic stroke is similar to that documented for the more common ischemic stroke (2.7 million), according to a systematic analysis in 2019 for the Global Burden of Disease Study (GBD 2016Stroke Collaborators, 2019. The case-fatality rate for ICH ranges from 35% at 7 days to 59% at 1 year, while 40% of survivors regain functional independence (de Oliveira et al, 2016;Tschoe et al, 2020;Zhang et al, 2022).…”