Protective effect of dapagliflozin against phenytoin-induced cerebellar dysfunction and histological alterations in rats: the role of SIRT1/Nrf2/HO-1 pathway.

Cerebellar dysfunction is a common issue emerges with long-term phenytoin use. This investigation was designed to test the protective role of sodium-glucose transporter 2 inhibitor (SGLT2I), dapagliflozin (DAPA) against cerebellar disorder accompanying phenytoin therapy in rats. Twenty-four adult male Wister rats were randomized into the control, phenytoin, and phenytoin + DAPA groups. Cerebellar functions were evaluated for all rats; then, cerebellar malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and heme oxygenase-1 (HO-1) were determined. Histopathological examination of rats' cerebelli and immunohistochemical analysis of cerebellar nuclear factor erythroid 2-related factor-2 (Nrf2) and silent information-regulated transcription factor 1 (SIRT1) were also conducted. Phenytoin-treated rats presented a marked cerebellar dysfunction in the form of increased ataxia score and disturbed footprints in relation to control rats. Besides, cerebellar MDA, TNF-α, and IL-6 were highly elevated, while cerebellar TAC and HO-1 were apparently reduced in phenytoin-treated rats. Histological features of cerebellar degeneration and atrophy were obviously detected as well as attenuated cerebellar expression of Nrf2 and SIRT1. Concomitant DAPA and phenytoin administration resulted in a clear amelioration in cerebellar functions and morphology with better redox and inflammatory conditions than phenytoin rats. It also enhanced the cerebellar expression of HO-1, Nrf2, and SIRT1. Eventually, inhibition of SGLT2 via DAPA could protect from the cerebellar damaging effect of phenytoin in rats. Such protective impression could be a result of combating cerebellar oxidative stress and inflammation and upregulation of cerebellar SIRT1/Nrf2/HO-1 axis pathway.