Glycocalyx Remodeling and Galectin-Mediated Inflammasome Activation as Convergent Drivers of Epileptogenesis and CNS Aging

Aging and epilepsy are increasingly recognized as disorders of neurovascular and immune dysregulation rather than purely neuronal pathologies. Here, we integrate evidence from glycobiology, neurovascular aging, and epilepsy research to propose a bidirectional convergence model linking glycocalyx remodeling with galectin-mediated inflammasome activation. Aging-associated glycan truncation reduces endothelial core 1 O-glycosylation, leading to glycocalyx thinning and compromised blood-brain barrier (BBB) integrity. This dysfunction facilitates infiltration of inflammatory mediators, promoting astrocyte activation and impaired glutamate uptake, thereby enhancing neuronal hyperexcitability and epileptiform activity. Conversely, seizures induce upregulation of galectin-3 (Gal-3) in activated microglia, amplifying inflammasome activation and pro-inflammatory cytokine release. These inflammatory signals further disrupt endothelial function and exacerbate BBB instability, reinforcing glycocalyx degradation. Increased exposure of N-acetyllactosamine residues on endothelial glycans may additionally enhance Gal-3 binding, including from microglial or extracellular sources, further promoting endothelial activation and barrier dysfunction. Collectively, these processes establish a self-amplifying neurovascular inflammatory loop that may contribute to epileptogenesis in aging. This framework identifies the glycocalyx-galectin axis as a potential mechanistic link and therapeutic target in aging-associated epilepsy.