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

## TL;DR

Memantine, an Alzheimer's drug, reduces seizures and brain damage in zebrafish, suggesting it could be repurposed to treat epilepsy.

## Contribution

Memantine shows multi-target effects in a zebrafish seizure model, including anticonvulsant, neuroprotective, and behavioral benefits.

## Key findings

- Memantine reduced seizure severity and delayed seizure onset in zebrafish.
- Memantine prevented GluN2A overexpression and reduced oxidative stress markers.
- Memantine reversed seizure-induced anxiety-like behavior in zebrafish.

## Abstract

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.

Approximately 30% of epilepsy patients do not respond to current medications. In addition, the pharmaceutical industry is reducing its interest in de novo drug discovery for epilepsy. Drug repurposing offers a promising alternative. This study investigated memantine, an Alzheimer's drug, in a zebrafish model of seizures. We found that memantine not only reduced seizure severity but also prevented key molecular consequences: the overproduction of a specific brain receptor (the GluN2A NMDA receptor subunit) and oxidative brain damage. Importantly, it also alleviated seizure‐induced anxiety‐like behavior. Our findings position memantine as a compelling multi‐target candidate for repurposing to treat epilepsy and its debilitating neuropsychiatric co‐morbidities.