Effects of fasudil against photothrombotic stroke in genetically modified obese (ob/ob) mice

Obesity and diabetes are major risk factors for ischemic stroke, leading to high comorbidity and poor recovery worldwide. Current treatments are not effective in stroke patients with obesity and diabetes because of their diverse modifying pathogenesis. However, Fasudil has emerged as a promising candidate with potential neuroprotective properties. Herein, we investigated the protective role of Fasudil in ischemic stroke using a genetically obese mouse model. Ischemic stroke was induced by the Rose Bengal photothrombosis method in adult obese mice (C57BL/6J-ob/ob; B6. Cg-Lepob/J; 9-10 weeks old). Fasudil (10 mg/kg b.w.) was administered intraperitoneally at 30 min, 24 h and 48 h following stroke. The blood glucose and rotarod tests were performed, and mice were euthanized at 72 h after stroke for molecular analysis. Fasudil treatment reduced infarct volume and ipsilateral brain edema, and downregulated thioredoxin-interacting protein and NOD-like receptor pyrin domain-containing-3 inflammasome. Additionally, it attenuated oxidative stress, downregulated Rho-kinase A protein expression, and reduced the number of TUNEL-positive cells in the ipsilateral area. These protective effects of Fasudil were accompanied by improved blood-brain barrier integrity markers and reduced levels of phosphorylated JNK and P75NTR. Collectively, these findings suggest that Fasudil confers neuroprotective effects following stroke in genetically modified obese (ob/ob) mouse model, independent of glycemic modulation. This study highlights the potential of Fasudil as a therapeutic target for acute ischemic stroke in the context of obesity and metabolic dysfunction, warranting further investigation in preclinical and clinical settings, particularly in patients with obesity and diabetes.