Neuroprotective effects of atorvastatin through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms against transient ischemic/reperfusion injury in diabetic rats

Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Atorvastatin plays an important role in the maintenance of hyperlipidemia especially in diabetic patients. Debate continues about the best strategies for management of diabetic stroke. Thus, interest was raised to investigate the neuroprotective effects of atorvastatin against transient ischemia/reperfusion (I/R) injury in diabetic rats targeting mainly the oxidative-inflammatory-apoptotic cascade which has been previously addressed as co-conspirators in this insult. Forebrain ischemia was induced in streptozotocin-diabetic rats by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Atorvastatin (15 mg/kg; p.o) was administered daily for 2 weeks prior to I/R injury. The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa NF-κB, 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 atorvastatin 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 NF-B signaling pathway as well as improved oxidant status. Atorvastatin exerted an anti-apoptotic effect as reflected by the reduction of the cytosolic cytochrome c and the key downstream executioner caspase-3. In conclusion, atorvastatin is gifted 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.