Synergistic Attenuation of Combined CBD Oil and Low Dose Valproic Acid in PTZ-Induced Seizure and in-silico Analysis

Background and Objective: Epilepsy is one of the most prevalent Central Nervous System (CNS) disorders that affects society and the healthcare system. However, control of seizure therapeutically with the use of old-generation antiepileptic agents, such as valproic acid (VPA), comes with severe adverse effects as they all have low therapeutic index. This study aims to investigate the synergetic effect of Cannabidiol oil (CBD oil) combined with low-dose valproic acid in pentylenetetrazol (PTZ)-induced seizures in rats. Materials and Methods: Forty-two animals were divided into six treatment groups: PTZ only (75 mg/kg), CBD only (50 mg/kg), VPA only (100 mg/kg), protective group, CBD (50 mg/kg)+VPA (75 mg/kg) for 1 week and two lower doses of VPA (50 and 75 mg/kg), respectively with CBD (50 mg/kg). Administration of drugs was by intraperitoneal (IP) route. The procedure was repeated three times on separate days and the time of seizure onset, duration, recurrence and mortality were measured. Data were analyzed using Two-way Analysis of Variance (ANOVA) and statistical difference was taken at p<0.05. Results: The onset of seizure was significantly longer in CBD+VPA combination treatment (50+75 mg/kg) and VPA (100 mg/kg) group compared to other groups. The combination also exhibited the shortest seizure duration, compared VPA (100 mg/kg) treatment. No mortality was recorded in these groups even after 72 hrs. Molecular docking studies confirmed that CBD and VPA bind on the same GABA subsite SER 267, indicating a synergism with VPA. Conclusion: Overall, these findings provide a critical and innovative approach to using low-dose VPA in combination with CBD oil. Therefore, developing a combination of CBD oil and VPA could potentially decrease dose-associated side effects yet enhance the therapeutic effectiveness preferably through synergism effects.