Research ArticleNeuroscience

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein

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Science Signaling  11 Dec 2018:
Vol. 11, Issue 560, eaat4285
DOI: 10.1126/scisignal.aat4285

Treating stroke with miRNA mimics

The loss and subsequent return of blood flow in the brain that occurs with a stroke (called ischemia-reperfusion) damages brain tissue and, consequently, can be lethal or severely impair cognitive and motor functions. Kim et al. found that treating rodents with an oligonucleotide mimicking the microRNA miR-7 either before or within 30 min (but not 2 hours) after focal cerebral ischemia reduced the amount of brain damage and improved motor recovery. The mimic appeared to work by repressing expression of the protein α-synuclein, which is associated with neuronal death in various diseases. These findings suggest that rapid treatment with the miR-7 mimic, or possibly preventive treatment in those at high risk, may prevent brain damage and improve quality of life after a stroke.

Abstract

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic–dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

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