TY - JOUR
T1 - Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats
AU - Yu, Jing
AU - Wang, Wen Na
AU - Matei, Nathanael
AU - Li, Xue
AU - Pang, Jin Wei
AU - Mo, Jun
AU - Chen, Sheng Pan
AU - Tang, Ji Ping
AU - Yan, Min
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2020 Jing Yu et al.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Oxidative Stress/drug effects
KW - Animals
KW - Cell Cycle Proteins/metabolism
KW - NF-E2-Related Factor 2/metabolism
KW - Rats
KW - Male
KW - Inflammation/drug therapy
KW - AMP-Activated Protein Kinases/metabolism
KW - Ezetimibe/pharmacology
KW - Infarction, Middle Cerebral Artery/drug therapy
KW - Rats, Sprague-Dawley
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85077998263&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077998263&partnerID=8YFLogxK
U2 - 10.1155/2020/4717258
DO - 10.1155/2020/4717258
M3 - Article
C2 - 31998437
SN - 1942-0900
VL - 2020
JO - Oxidative Medicine and Cellular Longevity
JF - Oxidative Medicine and Cellular Longevity
M1 - 4717258
ER -