Effect of solid lipid nanoparticles loaded with valproate and metformin on pentylenetetrazole-induced epilepsy in rats.

Abstract

Valproate is a first-line therapy for epilepsy. It enhances GABA-mediated inhibition by increasing GABA synthetase enzyme activity. However, it causes hepatotoxicity. Metformin, a biguanide derivative that lowers glucose, is given for type 2 diabetes. There have been reports of its potential to protect the liver. Recent studies show that metformin activates AMPK, which improves lithium- and pilocarpine-induced status epilepticus in rats. Hence, the present study investigated the anti-epileptic activity of valproate- and metformin-encapsulated solid lipid nanoformulation against pentylenetetrazole-induced epileptic rats. The valproate- and metformin-loaded solid lipid nanoparticles were prepared using the solvent evaporation method followed by the ultra-sonication method. Stearic acid and glyceryl monostearate concentrations (2-10%) were employed as solid lipids. The formulated valproate- and metformin-loaded solid lipid nanoparticles were evaluated for their antiepileptic activity using pentylenetetrazole-induced epileptic rats. The 6% stearic acid shows better entrapment efficacy, zeta potential, particle size, and surface morphology. So, the same formulation was evaluated for its antiepileptic activity against pentylenetetrazole-induced epileptic rats. The duration and severity of convulsions were significantly decreased in solid lipid nanoparticle-treated epileptic rats. Also, valproate- and metformin-loaded solid lipid nanoparticles treated in epileptic rats increased the GABA, and serotonin levels, and decreased glutamate levels. The current study shows that valproate and metformin do not protect rats against convulsions better than valproate alone. However, the nanoformulation with lower dosage enhances bioavailability and acts similarly to valproate, reducing dose-related toxicity.