IMPROVING SEIZURE CONTROL IN DRUG-RESISTANT EPILEPSY: NOVEL EFFECTS OF INDOLE-3-CARBINOL AND BERBAMINE ON PHENYTOIN THERAPY

Approximately 30% of patients with epilepsy continue to experience uncontrolled seizures despite appropriate antiepileptic treatment. Drug-resistant epilepsy accounts for nearly 40% of sudden unexpected death in epilepsy cases, highlighting the need for improved seizure control strategies.Overexpression of P-glycoprotein (P-gp) is a major contributor to pharmacoresistance. This study investigated whether inhibition of P-gp by indole-3-carbinol (I3C) and berbamine (BBM) enhances the antiepileptic efficacy of phenytoin, by improving drug penetration, modulating epileptogenic pathways, and optimizing therapeutic outcomes. We established a rat model of MTLE, representing medically refractory epilepsy, by intracerebroventricular administration of kainic acid (0.625 µg). Seizure activity following combined treatment with phenytoin and I3C or BBM was assessed using electroencephalography and Racine behavioural scoring. We also conducted biochemical analyses to evaluate their effects on oxidative stress and inflammation.Phenytoin alone (50 mg/kg, ip, 14 days) worsened seizures, producing the highest EEG spike frequency and amplitude during the acute post-induction period. In contrast, co-administration of phenytoin with P-gp inhibitors—verapamil (25 mg/kg), I3C (75 mg/kg), or BBM (100 mg/kg)—significantly reduced seizure severity, as reflected by increased seizure latency and decreased seizure frequency, amplitude, and total seizure duration, compared with both the KA-control and phenytoin-alone groups(p<0.05).These combinations also attenuated inflammation and oxidative stress in serum and brain samples. To our knowledge, there are no previous studies evaluating the pharmacological effects of I3C and BBM in epilepsy. This study provides the first comprehensive evaluation of I3C and BBM in drug-resistant epilepsy, demonstrating that their P-gp-inhibitory, antioxidant, anti-inflammatory, and neuroprotective effects may enhance phenytoin efficacy.