Neuroprotective effects of pioglitazone against transient cerebral ischemic reperfusion injury in diabetic rats: Modulation of antioxidant, anti-inflammatory, and anti-apoptotic biomarkers

Abstract

Background

Recent growing consensus introduced thiazolidinediones, agonists of the nuclear receptor peroxisome proliferator-activated receptor gamma as promising candidates in the management of ischemia in various organs. Thereby, interest was raised to investigate the neuroprotective effects of pioglitazone against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative-inflammatory-apoptotic cascades which are involved in this insult.

Methods

Forebrain ischemia was induced in streptozotocin-diabetic rats by occlusion of the bilateral common carotid arteries for 15 min followed by 1 h reperfusion. Pioglitazone (10 mg/kg; po) was administered daily for 2 weeks prior to I/R.

Results

The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NFκB), 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 pioglitazone was depicted, where it reduced neutrophil infiltration, lipid peroxides, nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NFκB signaling pathway as well as improved oxidant status. Pioglitazone exerted an anti-apoptotic effect as reflected by the reduction of the cytosolic cytochrome c and the key downstream executioner caspase-3.

Conclusions

Pioglitazone is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms hence may provide a successful agent for the management of ischemic stroke.