Ginsenoside Rc attenuates cerebral ischemia-reperfusion injury in mice by regulating AMPK pathway-mediated pyroptosis
AIM:To comprehend the mechanism by which ginsenoside Rc protects against cerebral ischemia-reperfusion injury(CIRI),with a particular emphasis on pyroptosis.METHODS:The C57BL/6 mice were randomly di-vided into 6 groups:sham group,middle cerebral artery occlusion/reperfusion(MCAO/R)group,ginsenoside Rc+MCAO/R group(Rc group),AMP-activated protein kinase(AMPK)agonist acadesine/5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside(AICAR)+MCAO/R group(agonist group),and ginsenoside Rc+MCAO/R+AMPK inhibitor Compound C group(Rc+inhibitor group).The mice in agonist group were given 500 mg/kg of AICAR intraperitoneally,while those in Rc+inhibitor group were given 20 mg/kg of Compound C intraperitoneally.Ginsenoside Rc was gavaged into the mice in Rc and Rc+inhibitor groups at a dose of 40 mg/kg once per day for 7 d after modeling,while the mice in sham and MCAO/R groups got the same volume of purified water.With the use of the Zea-Longa score,we determined which mice had neu-rological abnormalities.TTC staining was employed for assessing the cerebral infarct amount in mice,and the dry wet weight technique was utilized for determining the degree of cerebral edema.Moreover,HE staining was used to observe pathological alterations in the brain,and Western blot and RT-qPCR were applied for detecting the expression of AMPK,nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1 and gasdermin-D(GSDMD)in the brains of mice.Lastly,ELISA was employed for measuring the levels of inflammatory factors,interleukin-1β(IL-1β)and IL-18.RESULTS:Brain edema,infarct volume and neurological impairments were all diminished in agonist and Rc groups.Additionally,they demonstrated neuronal damage inhibition.The ratio of p-AMPK/AMPK and AMPK mRNA ex-pression in mouse brain tissues was elevated in both Rc and agonist groups.They showed decreased mRNA and protein levels of NLRP3,caspase-1 and GSDMD,as well as the levels of IL-1β and IL-18.Compared with Rc group,there were remarkable decreases in p-AMPK/AMPK ratio and AMPK mRNA expression in the brain tissue of mice in Rc+inhibitor group(P<0.05).The mRNA and protein levels of NLRP3,caspase-1 and GSDMD,and the IL-1β and IL-18 expression levels were significantly increased(P<0.05).Moreover,the neurological deficiency scores and infarct volume were in-creased,and the degrees of cerebral edema and neuronal pathological damage were enhanced(P<0.05).CONCLU-SION:Ginsenoside Rc may inhibit NLRP3/caspase-1/GSDMD-mediated pyroptosis by activating AMPK pathway,thereby reducing CIRI in mice.
ginsenoside Rccerebral ischemia-reperfusion injuryAMP-activated protein kinasepyroptosis
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