Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPKNrf2TXNIP Pathway after MCAO in Rats

Abstract EN

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.