Involvement of H₂S, NO and BDNF‐TrkB signalling pathway in the protective effects of simvastatin against pentylenetetrazole‐induced kindling and cognitive impairments in mice

Cognitive dysfunction was observed in pentylenetetrazole (PTZ)‐kindled mice. The potential effectiveness of simvastatin (SIM) on PTZ‐induced kindling and cognitive impairments in mice was evaluated. The influence of SIM on hydrogen sulphide (H 2 S), nitric oxide (NO), reactive aldehydes and brain‐derived neurotrophic factor/tyrosine receptor kinase B (BDNF‐TrkB) signalling was also investigated. Kindling and cognitive impairments in mice were induced by 12 ip injections of PTZ (35 mg/kg) once every alternate day. The levels of reactive aldehydes and nitrite were increased while H 2 S was decreased in PTZ‐treated mice. These results were accompanied by a reduction in the gene expression of aldehyde dehydrogenase 2, cystathionine β‐synthase, BDNF and TrkB. In PTZ‐kindled mice, a rise in brain inducible nitric oxide synthase protein expression associated with histopathological changes was observed. SIM administration (1, 5 and 10 mg/kg, daily orally) along with alternate day of PTZ (35 mg/kg) resulted in a decrease in PTZ‐induced kindling with a dose‐dependent improvement in cognitive function. SIM (10 mg/kg) prevented, to variable extent, the disturbances associated with PTZ‐kindled mice with cortical, cerebellar and hippocampal structural improvement. These results suggested that SIM triggers multiple mechanisms that improve cognitive function in PTZ‐kindled mice through modulation of oxidative stress, H 2 S, NO and BDNF‐TrkB signalling pathway.