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Updated: Dec 11, 2025
An In Vivo Assessment of Blood-Brain Barrier Disruption in a Rat Model of Ischemic Stroke
Published on: March 11, 2018
MicroRNA-182 exacerbates blood-brain barrier (BBB) disruption by downregulating the mTOR/FOXO1 pathway in cerebral
Tongshuai Zhang1,2, Chao Tian1,3, Jinrong Wu1,4
1Department of Neurobiology, Harbin Medical University, Harbin, China.
Abstract:
Cerebral ischemia causes damage to the structure and function of the blood-brain barrier (BBB) and alleviating BBB destruction will be of great significance for the treatment and prognosis of ischemic stroke. Recently, microRNAs have been shown to play a critical role in BBB integrity. However, the potential mechanism by which microRNA-182 (miR-182) affects the BBB in ischemic stroke remains unclear. We demonstrated for the first time that cerebral ischemia leads to a significant progressive increase in miR-182 after pMCAO, and bEnd.3 cells are the primary target cells of miR-182. In miR-182 KD transgenic mice, infarct volume, and BBB permeability were attenuated, and tight junction (TJ) proteins increased. Inhibition of miR-182 with an antagomir reduced OGD-induced apoptosis of bEnd.3 cells and the loss of ZO-1 and Occludin. To further explore the mechanism by which miR-182 regulates BBB integrity, we detected the apoptotic proteins Bcl-2/Bax and demonstrated that mTOR and FOXO1 were the targets of miR-182. Inhibition of mTOR/FOXO1 by rapamycin/AS1842856 decreased the ratio of Bcl-2/Bax and exacerbated TJ protein loss. Taken together, inhibition of miR-182 protects BBB integrity by reducing endothelial cell apoptosis through the mTOR/FOXO1 pathway. Thus, miR-182 may be a potential target for the treatment of BBB disruption during cerebral ischemia.
Insights
Inhibition of microRNA-182 (miR-182) protects the blood-brain barrier (BBB) after ischemic stroke by reducing endothelial cell apoptosis. This finding suggests miR-182 is a potential therapeutic target for stroke treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- Cerebral ischemia damages the blood-brain barrier (BBB), impacting stroke prognosis.
- MicroRNAs are critical regulators of BBB integrity.
- The specific role of microRNA-182 (miR-182) in ischemic stroke-induced BBB damage is not fully understood.
Purpose of the Study:
- To investigate the mechanism by which miR-182 affects BBB integrity during cerebral ischemia.
- To determine if miR-182 is a potential therapeutic target for mitigating BBB damage in ischemic stroke.
Main Methods:
- Investigated miR-182 levels in a mouse model of ischemic stroke (pMCAO).
- Utilized miR-182 knockdown (KD) transgenic mice and antagomir inhibition.
- Assessed BBB permeability, infarct volume, tight junction protein expression (ZO-1, Occludin), and endothelial cell apoptosis (bEnd.3 cells).
- Explored the involvement of the mTOR/FOXO1 pathway and apoptotic proteins (Bcl-2/Bax).
Main Results:
- Cerebral ischemia significantly increased miR-182 levels, with bEnd.3 cells being primary targets.
- miR-182 KD mice showed reduced infarct volume and BBB permeability, with increased tight junction proteins.
- Inhibition of miR-182 decreased OGD-induced apoptosis and loss of ZO-1 and Occludin in bEnd.3 cells.
- mTOR and FOXO1 were identified as miR-182 targets; their inhibition exacerbated TJ protein loss.
Conclusions:
- Inhibition of miR-182 protects BBB integrity by reducing endothelial cell apoptosis via the mTOR/FOXO1 pathway.
- miR-182 represents a promising therapeutic target for treating blood-brain barrier disruption in cerebral ischemia.
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