Memantine Confers Multi‐Target Protection in a Zebrafish Seizure Model: Attenuating Epileptic Behavior, GluN2A Overexpression, and Oxidative Stress

Drug repurposing represents a strategic approach to identifying multi-target therapies for complex disorders like refractory epilepsy. Memantine (MN), a well-tolerated N-methyl-D-aspartate receptor (NMDAR) antagonist with additional multi-target activities, is a promising candidate for repurposing. This study investigated the preventive effects of MN on pentylenetetrazol (PTZ)-induced seizures and its associated neurochemical and behavioral sequelae in adult zebrafish. Animals were pre-treated with MN (20 or 50 mg/kg, i.p.) or vehicle 1 or 2 h before PTZ exposure. Seizure behavior was assessed immediately, while neurochemical and behavioral analyses were conducted 24 h post-seizure. MN pre-treatment significantly attenuated seizure severity and delayed the onset of tonic-clonic seizures. Notably, MN prevented the PTZ-induced upregulation of the GluN2A NMDAR subunit and mitigated oxidative stress by reducing protein carbonylation and normalizing superoxide dismutase (SOD) activity. Furthermore, MN abolished the PTZ-induced increase in time spent in the white compartment of a light/dark test, a behavioral indicator of disrupted defensive responses. These results demonstrate that MN confers robust anticonvulsant, neuroprotective, and behavioral-stabilizing effects in a zebrafish seizure model. Our findings reinforce the potential of memantine as a novel multi-target adjunct therapy for mitigating the neurobehavioral consequences of epilepsy.