Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Abstract

Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.

Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

“…Beyond its powerful cholesterol lowering effects, the latest evidence shows that Ezetimibe has additional pleiotropic effects. In fact, Ezetimibe has been demonstrated to reduce oxidative stress through the activation of the AMP-activated protein kinase (AMPK)/Nrf2 pathway in animal models of nonalcoholic steatohepatitis [22] and ischemic stroke [23,24]. Furthermore, there are data showing that Ezetimibe can reduce the expression of ER stress markers in liver extracts of Zucker obese fatty rats [25] and that Ezetimibe may increase the glutathione content in rat livers subjected to IR [26].…”

AMPK/SIRT1 Pathway is Involved in Arctigenin-Mediated Protective Effects Against Myocardial Ischemia-Reperfusion Injury

“…Adiponectin (APN) was found to reduce oxidative stress and NLRP3 inflammasome activation after cerebral ischemia-reperfusion injury by regulating AMPK/GSK-3 ( Liu et al, 2020 ). Additionally, Yu J et al also found that Ezetimibe (Eze) reduces oxidative stress and subsequent neuroinflammatory response by activating AMPK/Nrf2/TXNIP pathways in MCAO rats ( Yu et al, 2020 ). These findings manifest that AMPK activation plays a protective role in ischemic brain injury.…”

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

“…Interestingly, the deletion of endothelial TXNIP in mice or in vivo anti-TXNIP treatment protects from oxidative stress and NLRP3 inflammasome activation [ 13 , 21 ]. Metformin or other compounds are also used to lower TXNIP aortic levels in vivo or endothelial levels in vitro in order to restrain NLRP3 activation and protect from endothelial dysfunction and cardiovascular risk factors [ 60 , 67 , 87 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. The regulation of the NLRP3 inflammasome by the TRX-TXNIP complex is believed to be controlled by Nrf2 and AMPK [ 60 , 102 , 103 , 104 , 106 , 107 ].…”

“…Metformin or other compounds are also used to lower TXNIP aortic levels in vivo or endothelial levels in vitro in order to restrain NLRP3 activation and protect from endothelial dysfunction and cardiovascular risk factors [ 60 , 67 , 87 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. The regulation of the NLRP3 inflammasome by the TRX-TXNIP complex is believed to be controlled by Nrf2 and AMPK [ 60 , 102 , 103 , 104 , 106 , 107 ]. The overexpression of TXNIP activates the TLR4-NF-κB-NLRP3 inflammasome signaling pathway with increased MyD88, NLPR3 inflammasome, and ASC expression, as well as the increased phosphorylation of lκBα and p65, thus promoting downstream NF-κB activation [ 109 ].…”