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Under physiological stressors\u2014depolarization, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload, redox shift, or cytokine exposure\u2014these large pores release adenosine triphosphate, glutamate, and other danger signals that activate P2X\/P2Y and N\u2010methyl\u2010D\u2010aspartate receptors, ignite NLR family pyrin domain containing (NLRP) 3 inflammasome, and propagate Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \/reactive oxygen species waves between mast cells, microglia, astrocytes, oligodendrocytes, neurons, and brain endothelium. Evidence across acute (e.g., stroke, trauma, seizure, and sepsis) and chronic (e.g., Alzheimer's, and multiple sclerosis) models shows that genetic ablation or pharmacological blockade of hemichannels shrinks lesions, preserves synaptic plasticity, restores blood\u2013brain barrier integrity, and rescues cognition, often without altering the primary pathogenic trigger. Translational leads include mimetic peptides (e.g., Gap19,\n                    <jats:sup>10<\/jats:sup>\n                    panx1), the nanomolar, gap junction\u2013sparing small\u2010molecule D4, and the pleiotropic alkaloid boldine, all of which curb epileptiform activity, neurodegeneration, and depressive\u2010like behavior. Yet key gaps persist, such as the long\u2010term safety of chronic inhibition, which remains poorly defined and will be critical to translate these \u201cgatekeeper\u201d channels into next\u2010generation neuro\u2013anti\u2010inflammatory therapeutics.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70237-toc-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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