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

Jing Yu, Wen Na Wang, Nathanael Matei, Xue Li, Jin Wei Pang, Jun Mo, Sheng Pan Chen, Ji Ping Tang, Min Yan, John H. Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number4717258
JournalOxidative Medicine and Cellular Longevity
Volume2020
DOIs
StatePublished - 2020

ASJC Scopus Subject Areas

  • Biochemistry
  • Aging
  • Cell Biology

Keywords

  • Oxidative Stress/drug effects
  • Animals
  • Cell Cycle Proteins/metabolism
  • NF-E2-Related Factor 2/metabolism
  • Rats
  • Male
  • Inflammation/drug therapy
  • AMP-Activated Protein Kinases/metabolism
  • Ezetimibe/pharmacology
  • Infarction, Middle Cerebral Artery/drug therapy
  • Rats, Sprague-Dawley
  • Disease Models, Animal

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