MicroRNA Regulatory Network as Biomarkers of Late Seizure in Patients with Spontaneous Intracerebral Hemorrhage.

ABSTRACT

Approximately 15% of patients experience seizures after spontaneous intracerebral hemorrhage (ICH). The pathogenesis of seizures post-ICH is not well-known; however, iron deposition-related neuronal injury following hemoglobin breakdown may contribute. Profiling known miRNAs to identify biomarkers for post-ICH late seizures, we found 64 differentially expressed miRNA 32 upregulated and 32 downregulated in seizure vs. non-seizure. Functional classification of upregulated miRNA for KEGG pathways and biological processes identified enrichment for cell cycle, protein modifications, and FoxO neurotrophin signaling pathways. No significant enrichment was found for downregulated miRNA. Molecular functions Gene Ontology (GO) terms enriched for upregulated miRNA are numerous, while downregulated miRNAs were associated with ion channel activity. RT-PCR confirmed two miRNAs, 4317 and 4325, were differentially expressed in patients who developed seizures at 1 year. MiR-4317 regulates SLC38A1, a glutamine-glutamate transporter. Integrated miRNA-mRNA network analysis identified COMMD6, APOBEC2, and RASSF6-involved in NF-kB regulation. Two miRNAs (miR-4317 and 4325) differentiated post-ICH late seizures vs. non-seizures at 1 year. The results suggest functional and miRNA-mRNA networks as potential biomarkers for post-ICH late seizures.