Abstract
Toll-like receptors (TLRs) play key roles in cerebral ischemia and reperfusion injury by inducing the production of inflammatory mediators, such as interleukins (ILs) and tumor necrosis factor-alpha (TNF-α). According to recent studies, ursolic acid (UA) regulates TLR signaling and exhibits notable anti-inflammatory properties. In the present study, we explored the mechanism by which UA regulates inflammation in the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model. The MCAO/R model was induced in male Sprague–Dawley rats (MCAO for 2 h, followed by reperfusion for 48 h). UA was administered intragastrically at 0.5, 24, and 47 h after reperfusion. The direct high mobility group box 1 (HMGB1) inhibitor glycyrrhizin (GL) was injected intravenously after 0.5 h of ischemia as a positive control. The degree of brain damage was estimated using the neurological deficit score, infarct volume, histopathological changes, and neuronal apoptosis. We assessed IL-1β, TNF-α, and IL-6 levels to evaluate post-ischemic inflammation. HMGB1 and TLR4 expression and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) were also examined to explore the underlying mechanism. UA (10 and 20 mg/kg) treatment significantly decreased the neurological deficit scores, infarct volume, apoptotic cells, and IL-1β, TNF-α, and IL-6 concentrations. The infarct area ratio was reduced by (33.07 ± 1.74), (27.05 ± 1.13), (27.49 ± 1.87), and (39.74 ± 2.14)% in the 10 and 20 mg/kg UA, GL, and control groups, respectively. Furthermore, UA (10 and 20 mg/kg) treatment significantly decreased HMGB1 release and the TLR4 level and inactivated NFκB signaling. Thus, the effects of intragastric administration of 20 mg/kg of UA and 10 mg/kg of GL were similar. We provide novel evidence that UA reduces inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly through the HMGB1/TLR4/NFκB signaling pathway.
Highlights
AND BACKGROUNDIschemic stroke, which occurs as a result of the sudden occlusion of a blood vessel by a thrombus or embolism, is a common cause of death and disability worldwide [1]
We provide novel evidence that ursolic acid (UA) reduces inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly through the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NFκB signaling pathway
We investigated whether UA reduced inflammatory cytokine production to protect the brain from cerebral ischemia and reperfusion injury possibly though the HMGB1/TLR4/NFκB signaling pathway
Summary
AND BACKGROUNDIschemic stroke, which occurs as a result of the sudden occlusion of a blood vessel by a thrombus or embolism, is a common cause of death and disability worldwide [1]. Thrombolysis therapy within the therapeutic window and mechanical thrombectomy in stroke patients are widely accepted for the treatment of sudden cerebral ischemia [2, 3]. Toll-like receptor 4 (TLR4) plays a key role in cerebral ischemia and reperfusion injury by inducing the production of inflamma tory mediators, such as interleukins (ILs) and tumor necrosis factor-alpha (TNF-α) [7, 8]. TLR4 were initially identified as receptors for endogenous ligands known as damage-associated molecular patterns (DAMPs), high mobility group box 1 (HMGB1), during brain injury. HMGB1 is a ubiquitous DNA-binding nuclear protein that is either passively released from necrotic cells or actively secreted in response to inflamma tory signals [9, 10]. Strategies that modulate post-ischemic TLR4 signaling in the brain may suppress inflammation induced by cerebral ischemia and provide new therapies for stroke
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