Fasudil mitigates diabetes-associated cognitive decline and enhances neuroprotection by suppressing NLRP3/Caspase-1/GSDMD signaling in a stroke mouse model

Type 2 diabetes mellitus and obesity are progressive metabolic disorders that heighten the risk of negative outcomes and cognitive decline after an ischemic stroke with limited treatment options. Previous research has shown that Fasudil, a RhoA kinase inhibitor, has therapeutic benefits in various neurological diseases; however, it is unknown if Fasudil provides neuroprotection in diabetic encephalopathy after ischemic stroke. This study aimed to explore the protective effects of Fasudil in an experimental model of diabetic encephalopathy following a photothrombotic stroke using high-fat diet-streptozotocin (HFD/STZ) mice to assess behavioral outcomes and molecular analysis. The experimental mice underwent photothrombotic stroke (pt-MCAO) surgery by retro-orbital injection of Rose Bengal (15 mg/kg), followed by 4 min exposure of the proximal-middle cerebral artery to a 532 nm laser exposure. The results indicated that Fasudil treatment provided potential neuronal protection and improved behavioral outcomes in post-stroke HFD/STZ mice. Additionally, Fasudil inhibited NOD-like receptor protein 3 (NLRP3) inflammasomes and their components, enhanced cognitive function by regulating synaptic markers, and significantly reduced neuroinflammation in post-stroke HFD/STZ mice. Fasudil also notably decreased oxidative stress and apoptosis by modulating Bax and cleaved PARP-1 protein expression and reducing the number of TUNEL-positive cells. In summary, Fasudil treatment offers neuroprotection and enhances cognitive function by preventing oxidative damage and NLRP3 inflammasome activation in post-stroke HFD/STZ mice. These results suggest that Fasudil may serve as a promising alternative therapeutic candidate for improving stroke outcomes and addressing the limitations of current treatment options.