Ondansetron reduces seizures and improves cognitive impairment in a rat model of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) remains an intractable chronic neurological disorder. Emerging evidence suggests a crucial modulatory role for the 5-hydroxytryptamine 3 receptor (5-HT₃R) in epilepsy. Ondansetron, a selective 5-HT₃ receptor antagonist widely used as an antiemetic, has demonstrated neuroprotective effects in preclinical models of several neurological disorders. However, its potential therapeutic efficacy in chronic TLE has not yet been investigated. In this study, we evaluated ondansetron's effects on spontaneous recurrent seizures (SRS), cognitive function, and hippocampal neurodegeneration in a pilocarpine-induced rat model of chronic TLE. Rats received three weeks of intraperitoneal ondansetron, after which spontaneous recurrent seizures (SRS), cognitive performance, and hippocampal neurodegeneration were assessed. Levels of key neurotransmitters (glutamate, GABA), markers of oxidative stress, and inflammatory cytokines were also measured. Ondansetron treatment significantly reduced SRS frequency, improved cognitive function, attenuated hippocampal impairment, and suppressed synaptic remodeling. It also lowered glutamate levels, neuroinflammation, and oxidative stress. The anti‑epileptic and neuroprotective effects of ondansetron in TLE may be attributed to its multi‑faceted properties, including anti‑inflammatory, anti‑oxidative, neurotransmitter‑modulating, and synaptic‑stabilizing properties. These findings highlight ondansetron as a promising candidate for adjunctive therapy in drug‑resistant TLE.