Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats

Abstract

There is a large body of evidence suggesting that inhibitors of dipeptidyl peptidase-4, such as sitagliptin, may exhibit beneficial effects against different inflammatory disorders. This investigation was conducted to elucidate the potential ability of sitagliptin to counteract the injurious effects of doxorubicin in cardiac tissue. Male Wistar rats were pretreated with sitagliptin for 10 days then treated with a single dose of doxorubicin (20 mg/kg, i.p). Electrocardiography, biochemical estimation of serum and tissue markers, and histo-and immunopathological examinations were done. Results have shown that supplementation with sitagliptin resulted in significant improvement of cardiac function with contaminant decrease in serum markers of doxorubicin-induced cardiotoxicity. These results were supported by the histopathological results. Furthermore, a marked protection against oxidative stress was evident through reduction of lipid peroxidation and prevention of reduced glutathione content depletion and superoxide dismutase activity reduction in cardiac tissue of rats pretreated with sitagliptin in combination with doxorubicin. Moreover, sitagliptin ameliorated the activation of nuclear factor kappa-B and the release of inflammatory cytokines, tumour necrosis factoralpha and nitric oxide. Finally, sitagliptin attenuated doxorubicin-induced increase in the expression of pro-apoptotic protein Bax and in the apoptotic marker, caspase-3. Collectively, these data indicate that sitagliptin pretreatment could alleviate doxorubicininduced cardiotoxicity via reducing oxidative damage and its subsequent inflammation and apoptosis.

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity

“…Sitagliptin pretreatment down-regulated iNOS expression and inhibited nitric oxide release. That inhibitory effect of sitagliptin against nitric oxide production is in agreement with previous studies [12]. …”

“…These changes were significantly ameliorated by sitagliptin pretreatment. These results are in accordance with previous investigations that reported the ability of sitagliptin to suppress apoptosis through modulation of apoptotic and anti-apoptotic proteins [12,21,32]. Enhancement of antioxidant status of the liver through Nrf2 activation, inhibition of NF-κB with subsequent inhibition of inflammatory cytokines and reduction of apoptosis through control of apoptotic and anti-apoptotic proteins promote hepatocyte survival against MTX toxicity.…”

“…Sitagliptin pretreatment showed marked inhibitory effect on NF-κB activation pathway. These results are in line with previous reports which showed the ability of sitagliptin to counteract NF-κB activation [12,29]. Taken together, these results clearly suggests for the first time that sitagliptin hepatoprotective role may be closely linked to its ability to modulate NF-κB and Nrf2 cross-talk.…”

“…The oxidative damage induced by MTX in liver tissue was prevented by sitagliptin pretreatment as it provided anti-oxidant effects not only on the non-enzymatic defense system (GSH), but also on the enzymatic one such as SOD. Similar antioxidant effects of sitagliptin were recently reported in many inflammatory conditions including myocardial injury [12,21], liver steatohepatitis [13,14], type 2 diabetes [22] and renal ischemia/reperfusion injury [23]. …”

“…This suggests that DPP-4 is involved in determining immune responses and procession of inflammatory disorders as well [9]. Recently, the anti-inflammatory action of sitagliptin has been reported in different types of cardiovascular injury [10–12]. Notably, sitagliptin has shown hepatoprotective activity in experimentally induced steatohepatitis via modulation of lipid metabolism, oxidative stress and inflammatory mediators [13,14].…”