Post-insult valproic acid-regulated microRNAs: potential targets for cerebral ischemia

Stroke is a devastating brain injury that is a leading cause of adult disability with limited treatment options. Using a rat model of middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, we profiled microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex. Many miRNAs were confirmed by qPCR to be robustly upregulated 24 hours following MCAO surgery including miR-155, miR-297a, miR-466f, miR-466h, and miR-1224. In addition, we treated MCAO rats with valproic acid (VPA), a mood stabilizer and histone deacetylase inhibitor. This post-insult treatment was shown to improve neurological deficits and motor performance following MCAO. To provide mechanistic insight into the potential targets and pathways that may underlie these benefits, we profiled miRNAs regulated following this VPA treatment. Two promising post-insult VPA-regulated candidates were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in rat cortical neuronal cultures subjected to oxygen-glucose deprivation, an in vitro ischemic model. The predicted targets of these miRNAs analyzed by Ingenuity Pathway Analysis (IPA) identified networks involved in hematological system development, cell death, and nervous system development. These predicted networks were further filtered using IPA and showed significant associations with neurological diseases including movement disorders, neurodegenerative disorders, damage to cerebral cortex, and seizure disorders among others. Collectively, these data support common disease mechanisms that may be under miRNA control and provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that may yield new therapies for neurological disorders.