Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOS/NO/NF-ΚB response and caspase-3/Bax activation in rats

Cyclophosphamide (CYP) is a classic DNA-interacting anticancer agent with broad application in chemotherapy. However, CYP cerebral neurotoxicity is a worrisome side effect for clinicians and patients. Strategies to mitigate the underlying oxidative inflammatory cascades and neuroapoptosis induced by CYP are urgently needed. Herein, we have repurposed an antidiabetic drug, sitagliptin (STG), for a possible abrogation of CYP-induced cerebral neurotoxicity in rats. Healthy rats were administered STG (20 mg/kg body weight) for 5 days prior to neurotoxicity induced by CYP (200 mg/kg body weight, ip) on day 5 only, and rats were sacrificed after 24 h post-CYP injection. CYP caused profound increases in the cerebral levels of nitric oxide (NO), acetylcholines-terase (AChE), malondialdehyde (MDA), interleukin-18 (IL-18), interleukin-6 (IL-6) and tumor necrosis factor -alpha (TNF-alpha), nuclear factor-kappaB (NF-Kappa B), inducible nitric oxide synthase (iNOS), caspase-3 and Bax pro-tein compared to the control. Furthermore, CYP markedly depressed the activities of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), along with levels of reduced glutathione (GSH) and nuclear factor erythroid 2-related factor2 (Nrf2) compared to the control (p < 0.05). Interestingly, STG pre-treatment inhibited the CYP-induced alterations in caspase-3, Bax, pro-inflammatory cytokines, NO, iNOS, AChE, NF-Kappa B, and restored the cerebral antioxidant apparatus, including the Nrf2 and histopathological abrasions. Therefore, these findings show that STG could be repurposed to prevent CYP-induced cerebral toxicity in the brain.

Automated summary

This study found that sitagliptin, an antidiabetic drug, can mitigate the cerebral neurotoxicity induced by cyclophosphamide (CYP) by inhibiting inflammatory reactions and reducing oxidative stress.