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Published on: June 10, 2013
Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss
Jeong-mi Moon1, Lijun Xu, Rona G Giffard
11] Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA [2] Department of Emergency Medicine, Chonnam National University School of Medicine, Gwangju, South Korea.
Abstract:
MicroRNA (miRNA), miR-181a, is enriched in the brain, and inhibition of miR-181a reduced astrocyte death in vitro and infarct volume after stroke in vivo. This study investigated the role of miR-181a in neuronal injury in vitro and hippocampal neuronal loss in vivo after forebrain ischemia. miR-181a levels were altered by transfection with mimic or antagomir. N2a cells subjected to serum deprivation and oxidative stress showed less cell death when miR-181a was reduced and increased death when miR-181a increased; protection was associated with increased Bcl-2 protein. In contrast, transfected primary neurons did not show altered levels of cell death when miR-181a levels changed. Naive male rats and rats stereotactically infused with miR-181a antagomir or control were subjected to forebrain ischemia and cornus ammonis (CA)1 neuronal survival and protein levels were assessed. Forebrain ischemia increased miR-181a expression and decreased Bcl-2 protein in the hippocampal CA1 region. miR-181a antagomir reduced miR-181a levels, reduced CA1 neuronal loss, increased Bcl-2 protein, and significantly prevented the decrease of glutamate transporter 1. Thus, miR-181a antagomir reduced evidence of astrocyte dysfunction and increased CA1 neuronal survival. miR-181a inhibition is thus a potential target in the setting of forebrain or global cerebral ischemia as well as focal ischemia.
Insights
Inhibition of microRNA-181a (miR-181a) protects brain cells from injury. Reducing miR-181a levels after forebrain ischemia improved neuronal survival and reduced damage, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNA-181a (miR-181a) is abundant in the brain and implicated in cell death.
- Previous studies suggest miR-181a inhibition reduces astrocyte death and stroke-related infarct volume.
Purpose of the Study:
- To investigate the role of miR-181a in neuronal injury and hippocampal loss following forebrain ischemia.
- To evaluate the therapeutic potential of inhibiting miR-181a in ischemic brain injury models.
Main Methods:
- Utilized cell cultures (N2a cells, primary neurons) and a rat model of forebrain ischemia.
- Manipulated miR-181a levels using mimics and antagomirs via transfection and stereotactic infusion.
- Assessed cell death, neuronal survival (hippocampal CA1 region), and protein levels (Bcl-2, glutamate transporter 1).
Main Results:
- In vitro, reducing miR-181a protected N2a cells from serum deprivation and oxidative stress, linked to increased Bcl-2.
- Forebrain ischemia in rats increased miR-181a and decreased Bcl-2 in the hippocampal CA1 region.
- miR-181a antagomir administration reduced miR-181a levels, decreased CA1 neuronal loss, increased Bcl-2, and preserved glutamate transporter 1.
Conclusions:
- miR-181a inhibition mitigates neuronal injury and promotes neuronal survival in models of forebrain ischemia.
- Targeting miR-181a presents a potential therapeutic strategy for global and focal cerebral ischemia.
- miR-181a antagomirs show promise in reducing astrocyte dysfunction and enhancing hippocampal neuron survival post-ischemia.
