Phytol Enhances Anticonvulsant Effect of Carbamazepine and Diazepam Against PTZ-Induced Convulsion in Chicks, Possibly Through Voltage-Gated Sodium Channel and GABAA Interaction Pathways

Abstract

The chlorophyll-derived diterpenoid phytol (PHY) is evident for its diverse biological effects, including neuroprotective activities in experimental animals. This study aims at the evaluation of anticonvulsant effects along with the possible mechanism of action of PHY through animal and in silico studies. For this, we performed pentylenetetrazole (PTZ)-induced convulsion tests in chicks and in silico studies against GABA_A receptor subunits and voltage-gated sodium channel (VGSC) receptors. PHY was tested at 25, 50, and 75 mg/kg with or without the standard drugs diazepam (DZP: 5 mg/kg) and carbamazepine (CAR: 80 mg/kg) using a vehicle as a control. Acute oral toxicity was evaluated in chicks per OECD guidelines by administering PHY (500–2000 mg/kg, p.o.) and monitoring for 48 h for mortality, toxicological signs, and behavioral changes. PHY exhibited a dose-dependent anticonvulsant effect, significantly increasing latency and reducing convulsion frequency and duration at 75 mg/kg. PHY (75 mg/kg) combined with CAR and DZP showed the most potent reduction in convulsion frequency and duration, indicating a synergistic effect. Acute toxicity tests in chicks confirmed safety up to 2000 mg/kg. In silico studies demonstrated that PHY had good binding affinity with both the GABA_A receptor (–6.5 kcal/mol) and VGSC (–7.0 kcal/mol), potentially contributing to its anticonvulsant action through GABAergic and sodium channel modulation. PHY showed significant anticonvulsant activity, likely via GABA_A and VGSC modulation, warranting further studies to clarify its mechanisms and assess its adjunct potential in drug-resistant convulsion management.