LRRC8A Mediates Ischemic Neuronal Injury by Potentiating NMDA Receptor Activity and Activating Mitochondrial Apoptotic Pathway

Brain ischemia induces neuronal apoptosis, a key event in stroke pathology, but the underlying mechanisms remain incompletely understood. This study investigates the role of the volume-regulated anion channel subunit leucine-rich repeat-containing protein 8 A (LRRC8A) in ischemia-induced neuronal damage. In a rat model of middle cerebral artery occlusion (MCAO) and in cultured neurons under oxygen-glucose deprivation (OGD), ischemia/hypoxia rapidly upregulated LRRC8A expression in apoptotic neurons. Knockdown of lrrc8a via small interfering RNA (siRNA) attenuated brain infarction, improved neurological deficits, and reduced neuronal apoptosis. Mechanistically, lrrc8a knockdown suppressed the activation of the mitochondrial Bax/Bcl-2/Caspase-9/Caspase-3 apoptotic pathway. Furthermore, lrrc8a knockdown reversed OGD-induced hyperactivation of NMDA receptors (NMDARs) and weakened the enhanced interaction between LRRC8A and the obligatory NMDAR subunit GluN1, which was predicted by structural modeling. These findings reveal that cerebral ischemia upregulates neuronal LRRC8A, which may promote NMDAR hyperactivity via interaction with GluN1, thereby triggering mitochondrial apoptosis. LRRC8A represents a potential therapeutic target for mitigating neuronal apoptosis in ischemic stroke.