4-Methylumbelliferone (4-MU) Improves Learning and Memory After Cerebral Ischemia/Reperfusion Injury in Rats

Stroke is the sixth leading cause of death and lifelong disability for millions of people in the United States. Cerebral ischemia leads to oxidative stress, excitotoxicity, inflammation, and apoptosis; additionally, impairment in memory and learning occurs in the majority of subjects with ischemic stroke. The lack of definitive treatment has sparked extensive research into novel therapeutic strategies, including the use of 4-methylumbelliferone (4-MU), a coumarin derivative with potential neuroprotective properties. The present study examines the impact of 4-MU on reducing cerebral ischemia-reperfusion (I/R) injury and learning and memory impairments in male Wistar rats.

Animals were exposed to middle cerebral artery occlusion (MCAO) and treated with a single dose of 4-MU (25 mg/kg) dissolved in 0.9% DMSO. An automated shuttle box and Morris water maze (MWM) tests were employed to evaluate learning and memory impairments. Western blot assay, TTC staining, and Nissl staining were used to measure protein expression, infarct volume, and cell death, respectively.

Treatment with 4-MU reduced infarct volume and improved learning and memory impairments by downregulating HAS1 and HAS2. 4-MU modulated the release of proinflammatory cytokines including TNF-α and IL-1β, as well as anti-inflammatory markers like IL-10, and reduced oxidative stress markers in the brain.

The neuroprotective effects of 4-MU against cerebral I/R injury can be attributed to the downregulation of HAS1 and HAS2.