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MicroRNA Regulatory Network as Biomarkers of Late Seizure in Patients with Spontaneous Intracerebral Hemorrhage
Ifeanyi Iwuchukwu1,2,3, Doan Nguyen4, Michelle Beavers4
1Neurocritical Care and Neurology, University of Queensland, Ochsner Clinical School, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans, LA, 70121, USA. iiwuch@lsuhsc.edu.
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.
Insights
Two specific microRNAs (miRNAs) were identified as potential biomarkers for predicting late seizures after intracerebral hemorrhage (ICH). These findings may help in understanding seizure development post-ICH.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Approximately 15% of patients develop seizures after spontaneous intracerebral hemorrhage (ICH).
- The exact mechanisms causing seizures post-ICH are unclear, but iron deposition and subsequent neuronal injury from hemoglobin breakdown are suspected contributors.
- MicroRNAs (miRNAs) are being investigated as potential biomarkers for predicting neurological outcomes after ICH.
Purpose of the Study:
- To identify specific miRNAs that can serve as biomarkers for predicting late-onset seizures in patients following intracerebral hemorrhage.
- To explore the functional pathways and molecular networks associated with differentially expressed miRNAs in post-ICH seizure development.
Main Methods:
- Profiling of known miRNAs in patients with and without seizures post-ICH.
- Functional enrichment analysis (KEGG pathways, Gene Ontology) of differentially expressed miRNAs.
- Reverse transcription-quantitative polymerase chain reaction (RT-PCR) to validate miRNA expression.
- miRNA-mRNA network analysis to identify regulatory interactions.
Main Results:
- 64 differentially expressed miRNAs were found: 32 upregulated and 32 downregulated in patients with seizures compared to those without.
- Upregulated miRNAs were enriched in cell cycle, protein modifications, and FoxO neurotrophin signaling pathways.
- Two miRNAs, miR-4317 and miR-4325, were confirmed to be differentially expressed at one year post-ICH and can distinguish between seizure and non-seizure groups.
- miR-4317 was found to regulate SLC38A1, a key transporter for glutamine-glutamate.
Conclusions:
- miR-4317 and miR-4325 show potential as predictive biomarkers for late seizures after intracerebral hemorrhage.
- The identified miRNA-mRNA networks, including those involved in NF-kB regulation, offer insights into the molecular mechanisms underlying post-ICH seizures.
- Further research into these miRNA signatures could lead to improved patient monitoring and therapeutic strategies.
