Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant.

Abstract

MicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17-92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes.

• Authors: Taylor E Branyan, Amutha Selvamani, Min Jung Park, Kriti E Korula, Kelby F Kosel, Rahul Srinivasan, Farida Sohrabji
• Journal: Translational stroke research (Transl Stroke Res) Vol. 13 Issue 3 Pg. 432-448 (06 2022) ISSN: 1868-601X [Electronic] United States
• PMID: 34570349 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• MIRN20 microRNA, rat
• MicroRNAs

Topics

• Animals
• Disease Models, Animal
• Female
• Infarction, Middle Cerebral Artery (genetics)
• Male
• MicroRNAs (genetics, metabolism)
• Neuroprotection
• Rats
• Stroke (genetics, metabolism)