Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway

WHOM do we talk to to get this tested in humans? 

How do you get ursolic acid?

Ursolic acid is available over the counter as a supplement. It is also present in food, such as apple peel, cranberry juice, grape skin, holy basil, rosemary, thyme, oregano, sage, and other herbs. Rosemary and sage have the highest content of ursolic acid, 3.0% and 1.8%, respectively.

Grape skin; good, that means your doctor should be prescribing red wine.

Don't do this! I'm not medically trained and thus know nothing. Nothing here suggests it travels thru the digestive system unchanged and is useful afterwards.

 

Ursolic Acid Ameliorates Inflammation in Cerebral Ischemia and Reperfusion Injury Possibly via High Mobility Group Box 1/Toll-Like Receptor 4/NFκB Pathway

Yanzhe Wang, Lei Li, Shumin Deng, Fang Liu and Zhiyi He*

• Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, China

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(not orally) 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.

Introduction and Background

Ischemic 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). Currently, thrombolysis therapy within the therapeutic window and mechanical thrombectomy in stroke patients are widely accepted for the treatment of sudden cerebral ischemia (2, 3). However, an inflammatory response has been shown to occur after thrombolysis, exacerbating the reperfusion injury (4–6). Therefore, studies aiming to identify an effective adjunct to treatments for cerebral ischemia and reperfusion injury deserve more attention.

Toll-like receptor 4 (TLR4) plays a key role in cerebral ischemia and reperfusion injury by inducing the production of inflammatory 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), particularly 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 inflammatory signals (9, 10). In addition, overactive microglia and reactive astrocytes in the ischemic region can aggravate ischemic damage after activation of the TLR4 signaling pathways (11). Therefore, strategies that modulate post-ischemic TLR4 signaling in the brain may suppress inflammation induced by cerebral ischemia and provide new therapies for stroke.

Ursolic acid (UA: 3b-hydroxy-urs-12-ene-28-oic acid), a natural pentacyclic triterpenoid, has been reported to exhibit biological activities in the brain, including anti-oxidative, anti-tumor, anti-rheumatic, anti-viral, and anti-inflammatory effects (12). Furthermore, UA also inhibited microglial and astrocyte activation and decreased the levels of TNF-α, IL-1β, and IL-6 in lipopolysaccharide-induced brain inflammation in mice with cognitive deficits (13). However, researchers have not determined whether UA protects against ischemia and reperfusion injury by antagonizing the HMGB1/TLR4 signaling pathway. In this study, we used glycyrrhizin (GL) as a positive control drug. GL is a direct HMGB1 inhibitor and the effective dose for treating cerebral ischemia and reperfusion injury has been established (14).

In the present study, we used the rat middle cerebral artery occlusion and reperfusion (MCAO/R) model with UA and GL to examine the mechanism by which UA regulates the inflammation response induced by ischemia and reperfusion. 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.

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