MicroRNAs in the pathophysiology and treatment of status epilepticus

David C. Henshall

MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.