Intranasally administered pitavastatin ameliorates pentylenetetrazol-induced neuroinflammation, oxidative stress and cognitive dysfunction

Aim: The present study aimed to evaluate the neuroprotective potential of intranasally administered pitavastatin in the PTZ-induced kindling model. Materials and methods: Subconvulsant dose of PTZ (35 mg/kg, i.p) was administered on an alternate day until the development of kindling. Behavioural test, biochemical tests and inflammatory cytokines were estimated. Comparative molecular docking study of sodium valproate (VPA) and pitavastatin was performed to predict the binding affinity with GABA(A) and GABA transaminase. Intranasally administered pitavastatin (0.5 mg/kg and 1 mg/kg) and VPA (200 mg/kg) were used to investigate its protective effect. Key findings: Comparative in-silico study showed docking score of -4.56 and -2.86 against GABA(A) receptor whereas - 5.56 and - 1.86, against GABA transaminase. Root mean square deviation (RMSD) of 0.39A and 0.55A was found for pitavastatin and VPA, respectively. The present study showed the dose-dependent protective effect of intranasally administered pitavastatin and oral VPA against PTZ-induced seizure, cognitive impairment, oxidative stress, and neuroinflammation. Significance: Our findings suggest that the intranasally administered pitavastatin is potential therapeutic approach to managing PTZ-induced kindling and associated comorbid conditions via its antioxidant, anti-inflammatory, and anticonvulsant potential. Further, pitavastatin can modulate GABA(A) receptor and GABA transaminase enzyme to ameliorate seizure. Meanwhile, more extensive studies are required to establish the molecular mechanism underlying the neuroprotective effect of pitavastatin.