Neuroprotective Potential of Saroglitazar Against Cerebral Ischemia/Reperfusion Injury in Sprague-Dawley Rats: Targeting HMGB-1/NF-κB Pathway.

Abstract

Stroke is an intricate oxidative and inflammatory response resulting from cerebral ischemia followed by reperfusion injury. Complex pathophysiology of stroke poses challenges for treatment. Peroxisome proliferator-activated receptor (PPAR) expression in the rat hippocampus is markedly elevated post cerebral ischemia/reperfusion (I/R) injury. Hence, saroglitazar, a dual PPAR-α/γ agonist, was investigated against cerebral I/R injury in rats. Male Sprague-Dawley rats were subjected to bilateral common carotid artery occlusion for 30 min and reperfusion for 3 days. During the reperfusion, animals were treated with vehicle or saroglitazar once a day for 3 days. The behavioral parameters were assessed, and animals were sacrificed to measure oxidative markers (malondialdehyde, superoxide dismutase, catalase, and reduced glutathione), inflammatory markers (interleukin-6, tumor necrosis factor-α, nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), and high mobility group box 1 (HMGB-1) protein, infarction, and histopathology changes. Following I/R injury, antioxidant enzymes were reduced, while nitric oxide and inflammatory markers were increased in the disease group. In the rat hippocampus, these changes led to neurobehavioral impairment and cerebral infarction. Saroglitazar improved the levels of antioxidants and reduced inflammation; 2,3,5-triphenyltetrazolium chloride stain and histopathological analysis revealed the neuroprotective effect of saroglitazar in the hippocampus region. The neuroprotective effects of saroglitazar were attributed to its activation of both PPAR-α and PPAR-γ. It improved antioxidant levels and inhibited proinflammatory cytokines by suppressing the HMGB-1/NF-κB signaling pathway. These findings underscore the potential of saroglitazar in mitigating cerebral I/R injury.