Stage-specific targeting of the GABAergic system in ischemic stroke: mechanisms and therapeutic strategies

Neural injury and functional recovery after ischemic stroke are strongly time dependent. The acute phase is dominated by energy failure, ionic disequilibrium, excitotoxicity, spreading depolarization, and amplification of inflammation; the subacute phase is characterized by progressive network reorganization and competing forms of plasticity; and the chronic phase predominantly involves adaptive remodeling of residual networks. As the principal inhibitory neurotransmitter system in the central nervous system, gamma-aminobutyric acid (GABA) does not exert uniformly protective or detrimental effects throughout the course of stroke. Instead, its effects are jointly determined by intervention timing, the cellular source of GABA, receptor subtype and synaptic or extrasynaptic localization, transporter and metabolic status, and chloride homeostasis. After summarizing GABA synthesis and metabolism, receptors, transporters, and chloride homeostasis, this review follows the temporal course of ischemic stroke to discuss the protective effects of GABAergic inhibition against excitotoxicity and neuroinflammation during the acute phase, the bidirectional effects of GABA and tonic inhibition during the subacute phase, and the relationships among GABAergic tone, intrahemispheric and interhemispheric network reorganization, and windows of plasticity during the chronic phase. We further summarize preclinical and clinical evidence for receptor modulators, agents targeting GABA or chloride transport, monoamine oxidase B inhibitors, and non-invasive brain stimulation. We emphasize that effective targeting of the GABAergic system requires modulation tailored to disease phase, cellular source, receptor subtype, and spatial context, rather than indiscriminate enhancement or suppression of GABAergic signaling.