Pretreatment with 4-methylumbilliferon improves anxiety-like behaviors and memory impairment in stressed rats via modulation of neuronal cell death and oxidative stress.

This work was done to investigate the ameliorating impact of 4-methylumbilliferon (4-MU) on spatial learning and memory dysfunction and restraint stress (STR)-induced anxiety-like behaviors in male Wistar rats and the underlying mechanisms. Thirty-two animals were assigned into 4 cohorts: control, 4-MU, STR, and STR+4-MU. Animals were exposed to STR for 4 h per day for 14 consecutive days or kept in normal conditions (healthy animals without exposure to stress). 4-MU (25 mg/kg) was intraperitoneally administered once daily to STR rats before restraint stress for 14 consecutive days. The behavioral tests were performed through Morris water maze tests and elevated-plus maze to examine learning/memory function, and anxiety levels, respectively. The levels of the antioxidant defense biomarkers (GPX, SOD) and MDA as an oxidant molecule in the brain tissues were measured using commercial ELISA kits. Neuronal loss or density of neurons was evaluated using Nissl staining. STR exposure could cause significant alterations in the levels of the antioxidant defense biomarkers (MDA, GPX, and SOD) in the prefrontal cortex and hippocampus, induce anxiety, and impair spatial learning and memory function. Treatment with 4-MU markedly reduced anxiety levels and improved spatial learning and memory dysfunction via restoring the antioxidant defense biomarkers to normal values and reducing MDA levels. Moreover, more intact cells with normal morphologies were detected in STR-induced animals treated with 4-MU. 4-MU could attenuate the STR-induced anxiety-like behaviors and spatial learning and memory dysfunction by reducing oxidative damage and neuronal loss in the prefrontal cortex and hippocampus region. Taken together, our findings provide new insights regarding the potential therapeutic effects of 4-MU against neurobehavioral disorders induced by STR.

Protective effects of 4-methylumbelliferone on myocardial ischemia/reperfusion injury in rats through inhibition of oxidative stress and downregulation of TLR4/NF-κB/NLRP3 signaling pathway.

Myocardial ischemia-reperfusion injury (MI/R) has been found to be one of the important risk factors for global cardiac mortality and morbidity. The study was conducted to inquire into the protective effect of 4-methylumbilliferon (4-MU) against MI/R in rats and clarify its potential underlying mechanism. Animals were divided into four groups (n = 15) including sham, MI/R, MI/R + vehicle, and MI/R + 4-MU. MI/R was established in Wistar rats by occluding the left anterior descending (LAD) coronary artery for 30 min. 4-MU (25 mg/kg) was injected intraperitoneally before the induction of reperfusion. Cardiac function, fibrosis, oxidant/antioxidant markers, and inflammatory cytokines were evaluated using echocardiography, ELISA, and Western blot assay. As a result of MI/R induction, a decrease in left ventricular contractile function occurred along with increased cardiac fibrosis and tissue damage. The serum levels of TNF-α, IL-1ß, and IL-18 increased, while IL-10 decreased. Oxidant/antioxidant changes were evident with increased MDA levels and decreased GSH, SOD, and CAT in the MI/R group. Furthermore, the protein levels of TLR4, NF-κB, and NLRP3 were significantly increased in the heart tissue of MI/R group. Treatment with 4-MU significantly prevented the reduction of cardiac contractile function and its pathological changes as a result of MI/R by inhibiting the increase of serum inflammatory factors and improving the oxidant/antioxidant balance probably through the TLR4/NF-κB/NLRP3 axis. The results of a current study showed that 4-MU had a potential ability to attenuate the cardiac injury by reducing oxidative stress and inflammation in a TLR4/NF-κB/NLRP3-dependent mechanism.