Mifepristone alleviates cerebral ischemia-reperfusion injury in rats by stimulating PPAR γ

X.-J. Wu, X.-H. Sun, S.-W. Wang, J.-L. Chen, Y.-H. Bi, D.-X. Jiang

Department of Neurology, Weihai Central Hospital of Shandong, Weihai, China. jdx_jiang163.com

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• Pharmacology

OBJECTIVE: To investigate the changes of peroxisome proliferator-activated receptor gamma (PPAR γ) in focal cerebral ischemia-reperfusion injury, and to explore the effect and mechanism of mifepristone on the cerebral ischemia-reperfusion injury.

MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats were selected, and the middle cerebral artery occlusion and reperfusion (MCAO/R) rat model was constructed using the longa’s suture-occluded method. The sham operation group was not inserted with occlusion sutures. All experimental rats were divided into four groups: the sham operation group (SHA group), the MCAO/R model group (MCR group), the mifepristone intervention group (MIF group) (3 mg/kg, intragastric administration), and the mifepristone + bisphenol A diglycidyl ether (BADGE) intervention group (MIF+BAD group) [3 mg/kg mifepristone (intragastric administration) + 30 mg/kg BADGE (intraperitoneal injection)]. The long’s scoring method (5 grades) was applied for scoring after reperfusion, at the time when the animals woke up, and at 48 h after awaking before execution, respectively. 48 h after the model was successfully established, triphenyl tetrazolium chloride (TTC) staining was performed to calculate the volume of cerebral infarction, and Nissl staining was conducted to observe the cranial nerve tissue morphology. Meanwhile, immune-histochemical staining was used to detect PPAR γ. Moreover, the protein expression levels of PPAR γ, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), matrix metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were examined by Western blotting (WB).

RESULTS: Mifepristone could significantly enhance the neurological function after cerebral ischemia-reperfusion injury, reduce the volume of cerebral infarction, and improve the morphology of nerve tissues in rats. The expression of PPAR γ in the brain tissues of rats after cerebral ischemia-reperfusion injury markedly declined, whereas mifepristone could remarkably increase the protein expression of PPAR γ. After mifepristone intervention, the protein levels of TNF-α, IL-1β, IL-6, MMP-2, and MMP-9 in the infarcted brain tissues of rats were markedly decreased, while the expression of the TIMP-1 protein was increased. When combined with BADGE, the effect of mifepristone was partially offset.

CONCLUSIONS: Mifepristone acts as a PPAR γ agonist, and relieves cerebral ischemia-reperfusion injury by restoring the balance between MMPs and TIMPs and inhibiting inflammatory cytokines.

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