Effect of Nobiletin on Experimental Model of Epilepsy

BACKGROUND: The effects of nobiletin, a plant-derived flavonoid was examined against pentylenetetrazole (PTZ)-induced seizures. The study also aimed to assess whether nobiletin potentiated the effects of antiepileptic drug clonazepam (CZP). METHODS: PTZ (92 mg/kg, subcutaneous) was used to induce seizures in mice. Treatment groups (n = 18/group) received nobiletin (12.5, 25, or 50 mg/kg) via oral gavage for 6 consecutive days and 45 min prior to PTZ injection. CZP (0.015-2.0 mg/kg) was administered 15 min prior to PTZ. Skeletal muscle strength was assessed by measuring grip strength and Chimney test was performed to study the motor performance in animals. TUNEL assay was done to study neuro-apoptosis. RT-PCR and Western blot analysis were performed for assessment of mRNA and protein expressions. RESULTS: Nobiletin and CZP improved muscle strength and motor coordination and reduced seizure severity significantly. The administration of nobiletin and CZP, individually or in combination, downregulated seizure-induced increases in apoptotic cell count and apoptotic protein expression, modulated the expression of gamma-aminobutyric acid (GABA)A and glutamate decarboxylase 65 and restored the glutamate/GABA balance. Nobiletin and CZP administration significantly upregulated phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling. CONCLUSION: Nobiletin exerted protective effect against seizures by regulating signaling pathways associated with epileptogenesis and potentiated the effects of CZP.