Piracetam attenuates cyclophosphamide-induced hepatotoxicity in rats: Amelioration of necroptosis, pyroptosis and caspase-dependent apoptosis

Cyclophosphamide (Cyclo) is an immunosuppressive and antineoplastic agent. The clinical use of Cyclo is limited by significant hepatotoxicity. Piracetam (Pira) is used to improve cognitive function. Pira possesses diverse physiological functions; however, the exact mechanisms of its activity are still non-elucidated.Forty rats were allocated in four groups. 1st group comprised normal rats; the remaining groups received single Cyclo dose (200 mg/kg/i.p.) on the experiment's 15th day. 2nd group comprised Cyclo-control rats. 3rd & 4th groups received Pira (100 & 300 mg/kg body weight) for 15 days.Cyclo administration resulted in deterioration of serum liver function tests and elevation of hepatic tissue concentration of P53, Nf-kβ, apoptosis-inducing factor-1, NLRP3 inflammasome, Bax; gene expression of receptor-induced protein-1 along with reduction of hepatic Bcl-2 concentration. Bax/Bcl-2 ratio headed for apoptosis. Cyclo administration also resulted in a severe deterioration of the hepatic histopathological picture and significant immunohistochemical expression of caspase-3, tumor necrosis factor-alpha (TNF-α) and Cyclooxygenase-2 (COX-2) in hepatic tissues versus the normal group. Pira significantly improved all the aforementioned parameters, reallocating the Bax/Bcl-2 ratio to anti-apoptosis. Moreover, Pira treatment amended Cyclo-induced histopathological abnormalities and significantly reduced caspase-3, TNF-α plus COX-2 immunoreactivity in hepatic tissues.The present work is the first to link Cyclo-induced hepatotoxicity to the activation of caspase-independent apoptosis (necroptosis), pyroptosis and caspase-dependent apoptosis signaling pathways. Pira treatment significantly ameliorated Cyclo-induced hepatotoxicity mainly via the amendment of necroptotic, pyroptotic and caspase-dependent apoptotic changes along with the histopathological deformities in rats' hepatic tissues.