BACKGROUND: Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal neuronal electrical activity. Increasing evidence suggests that circadian clock dysfunction contributes to seizure susceptibility and neuronal excitability. Melatonin, a major regulator of circadian rhythm, possesses antioxidant and neuroprotective properties that may influence seizure regulation. Cucurbitacin E (CuE), a triterpenoid compound with potent antioxidant and anti-inflammatory activities, has emerged as a potential therapeutic agent targeting circadian and oxidative pathways. This study investigated the effects of CuE on seizure activity, oxidative balance, melatonin levels, and circadian clock gene expression in a pentylenetetrazol (PTZ)-induced epilepsy model.
METHODS: Eighteen male C57BL/6 mice were randomly assigned to control, PTZ, and PTZ + CuE groups (baseline n = 6/group). PTZ (35 mg/kg/day, i.p.) was administered every other day for 12 days, while CuE (0.5 mg/kg/day, i.p.) was administered 30 min after PTZ injections. Two animals were excluded during the study, resulting in final group sizes of n = 6, n = 5, and n = 5, respectively. Seizure severity was assessed using Racine scoring, and locomotor activity was monitored using the LABORAS system with manual seizure validation. Serum melatonin, total antioxidant status (TAS), total oxidant status (TOS), and circadian clock gene expression (PER1, CRY1, CLOCK, BMAL1, RORA, and REV-ERBα) were analyzed.
RESULTS: PTZ significantly increased seizure severity, oxidative stress, melatonin levels, and disrupted clock gene expression, whereas CuE markedly reduced seizures, improved oxidative balance, normalized melatonin levels, and partially restored circadian gene expression. Significant correlations were identified between melatonin levels and multiple clock genes.
CONCLUSION: These findings demonstrate that CuE exerts anticonvulsant effects through integrated chronomodulatory and antioxidant mechanisms, supporting its potential as a multi-target therapeutic strategy for epilepsy management.
