Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

Abstract

BackgroundActivators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance.MethodsThe middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed.ResultsUA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect.ConclusionUA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.

Ursolic acid in health and disease

“…This occurs because UA could suppress the NF-kB-dependent pathways that are activated by tumor necrosis factor-alpha (TNF-α) or interleukin 1 beta (IL-1β). Similar results were obtained by Wang et al [ 20 ], who revealed the association between UA and MMP-2/-9 expression in a rat model of cerebral ischemia and reperfusion injury. In this study, the activities of MMP-2 and MMP-9 were suppressed by UA administration.…”

“…UA is isolated from the leaves of various plants (rosemary, marjoram, lavender, thyme, and organum), fruits (apple fruit peel), flowers, and berries [ 11 ]. UA mediates some pharmacological processes and modulates several signaling pathways to prevent the development of chronic diseases [ 12 13 ]; it exhibits antiinflammatory [ 14 ], anti-oxidant [ 15 ], anti-carcinogenic [ 16 ], antiobesity [ 17 ], anti-diabetic [ 18 ], cardioprotective [ 19 ], neuroprotective [ 20 ], hepatoprotective [ 21 ], anti-skeletal muscle atrophy [ 22 ], and thermogenic effects [ 8 ]. The mechanisms by which UA exerts these beneficial effects may involve regulation of the following: nuclear factor-kappa B (NF-kB) and apoptotic signaling in cancer cells, insulin signaling in adipose tissue, the expression of markers of cardiac damage in the heart, inflammation and the level of anti-oxidants in the brain, metabolic signaling and the level of oxidants in the liver, and atrophy signaling and metabolic signaling in skeletal muscles.…”

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

“…at doses of 10 and 20 mg/kg. This finding provides further evidence that UA could be an effective therapeutic agent for cerebral ischemia ( 17 , 33 ). Our findings provide new insights into the potential effects of UA on brain ischemia.…”

“…when the other treatment groups were administered UA or GL. (3) In the low-dose UA (L-UA) group ( n = 18), 10 mg/kg UA (purity ≥ 95.0%, Sigma-Aldrich, St. Louis, MO, USA) in distilled water containing 0.5% Tween-80 (ddH 2 O/0.5% Tween-80) was administered by oral gavage at 0.5, 24, and 47 h after reperfusion, according to previous studies clarifying the oral absorption rate and drug action time ( 15 – 17 ). (4) The high-dose UA (H-UA) group ( n = 18) was administered 20 mg/kg UA.…”

Pistacia Genus as a Potential Source of Neuroprotective Natural Products

“…In a subarachnoid hemorrhage rat model, UA treatment reduced early brain injury via reducing apoptosis and suppressing TLR4-mediated inflammatory factors, such as intercellular adhesion molecule-1 (ICAM-1), TLR4, NF-κB, IL-1β, TNF-α, IL-6, iNOS, and matrix metalloproteinase (MMP)-9 [127]. It also showed neuroprotective effects as an activator of PPARs in a rat model of cerebral artery occlusion and reperfusion and modulated the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the MAPK signaling pathway [128]. UA has also been shown to have anxiolytic, anticonvulsant, and antidepressant activities in mice via affecting the GABA-A receptor, especially acting on the benzodiazepine binding site of GABA receptors [129,130].…”