Eucalyptol (1,8-Cineole) Exhibits Anti-seizure Activity Potentially via Modulation of the Nitric Oxide Pathway

Background: Seizures remain a major therapeutic challenge, and novel neuroprotective agents are under investigation. Eucalyptol (1,8-cineole), a monoterpene ether with antioxidant properties, has shown neuroprotective potential; however, its anti-seizure mechanism is not fully elucidated. Objectives: The present study evaluated the anti-seizure effects of eucalyptol in a pentylenetetrazol (PTZ)-induced seizure model in mice and examined the involvement of the nitric oxide (NO) pathway. Methods: Seventy-two NMRI mice were randomly allocated into control and treatment groups. Eucalyptol (30, 100, 300, or 600 mg/kg, i.p.) was administered with or without L-NAME (10 mg/kg, non-selective NOS inhibitor) or L-arginine (45 mg/kg, NO precursor). Seizure thresholds were determined via intravenous PTZ infusion. Brain and serum samples were analyzed for malondialdehyde (MDA), total antioxidant capacity (TAC), NO content, and hippocampal inducible and neuronal (nNOS) NO synthase gene expression. Results: Eucalyptol at 300 and 600 mg/kg significantly increased seizure thresholds (25.26 ± 7.47 and 26.11 ± 4.64 mg/kg vs 10.15 ± 1.67 in control; P < 0.05). L-NAME enhanced the effect of 30 mg/kg eucalyptol, while L-arginine attenuated the effect at 600 mg/kg. Effective doses also reduced MDA, NO, and increased TAC levels and normalized iNOS expression in hippocampal tissue. Conclusions: Eucalyptol at higher doses delays seizure onset and mitigates oxidative stress, possibly via modulation of the nitrergic pathway. These findings support further investigation of eucalyptol as a candidate for seizure management.