Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: implication of the oxidative-inflammatory-apoptotic pathway

Abstract

Aims: Ischemic stroke is a major macrovascular complication of diabetes mellitus. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, was recently shown to improve cognitive functions in diabetic rats; hence the present study was conducted to evaluate its protective effect against transient ischemia-reperfusion (I/R) in diabetic animals.

Main methods: Diabetes was induced by streptozotocin (40 mg/kg). Six weeks later, cerebral I/R was induced by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Sitagliptin (250 mg/kg; p.o.) was administered daily during the last 2 weeks before I/R.

Key findings: The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NF-κ)B, and consequently the downstream inflammatory cytokines tumor necrosis factor-α and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of sitagliptin was depicted, where it reduced neutrophil infiltration, lipid peroxides and nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NF-κB signaling pathway as well as improved oxidant status. Sitagliptin exerted an anti-apoptotic effect as reflected by the reduction of the mitochondrial matrix component cytochrome -C and the key downstream executioner caspase-3. Histopathological examination corroborated the biochemical data.

Significance: These findings suggest that sitagliptin is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms and hence may provide a novel agent for the management of ischemic stroke in diabetics.

Keywords: Apoptosis; Cytokines; Hippocampus; Ischemia/reperfusion; Sitagliptin; Streptozotocin.