Background: Epilepsy is a prevalent neurological disorder characterized by transient brain dysfunction due to abnormal neuronal discharges. Oxidative stress is strongly correlated with epilepsy onset and progression and is a critical factor in triggering seizures. Therefore, antioxidants may serve as effective anti-seizure treatments. Cerium oxide nanoparticles (CNP), which have antioxidant properties and function as nano-enzymes, may offer neuroprotective and therapeutic benefits for epilepsy. This study aims to investigate the effects of CNP on epilepsy.

Methods: We established a pilocarpine (PILO)-induced epilepsy rat model to assess the effects of pretreatment with different doses of CNP on epileptic behavioral changes, electroencephalographic activity, and nuclear factor erythroid 2-related factor 2 (NRF2) signaling in rats.

Results: In brief, a dose of 2.5 mg/kg CNP prolonged the latency of PILO-induced seizures in rats (p < 0.05), reduced the severity of seizures (p < 0.05), and decreased the 24-h mortality rate (p < 0.01). Additionally, CNP also extended the latency of epileptiform discharges (p < 0.01) and significantly decreased the average energy density of electroencephalographic activity (p < 0.0001). It inhibited seizure-induced lipid peroxidation (p < 0.001) and increased superoxide dismutase (p < 0.05) and catalase activities (p < 0.01). Furthermore, pretreatment with CNP elevated the expression of NRF2 and NADPH:quinone oxidoreductase 1 (NQO1) in antioxidative stress pathways (p < 0.05) and reduced neuronal necrosis and degeneration in CA1 and CA3 regions (p < 0.05).

Conclusions: CNP exhibits anti-epileptic and neuroprotective effects in PILO-induced epilepsy. This protective effect is likely due to the enhancement of the NRF2 signaling pathway, which regulates antioxidant enzymes, improves neuronal defense mechanisms against oxidative stress, and reduces seizure-induced neuronal damage.