The Promising Epigenetic Regulators for Refractory Epilepsy: An Adventurous Road Ahead

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Refractory epilepsy, such as Dravet Syndrome, lacks effective treatments, with recurrent seizures negatively impacting neural cell sub-genomic architecture.
• Current antiseizure drugs (ASDs) have limited genomic action, and seizure triggers remain poorly understood, contributing to persistent seizures.
• Recurrent seizures disrupt the serotonin pathway, cause CNS gene hypomethylation, and alter microRNA (miRNA)/long non-coding RNA (lncRNA) expression, leading to persistent molecular changes.

Purpose of the Study:

• To investigate the potential of epigenetic regulators (EGRs) from breast milk (BML) and Bacopa monnieri (BMI) in counteracting molecular alterations in refractory epilepsy.
• To explore how BML and BMI-derived EGRs, specifically miRNAs and lncRNAs, might mitigate the effects of SCN1A mutations in Dravet Syndrome.
• To propose mechanisms by which these EGRs could restore normal neuronal function and potentially improve cognitive deficits.

Main Methods:

• Analysis of miRNA and lncRNA profiles in BML and BMI.
• Identification of specific miRNAs within BML (miRNA-155-5p, -30b-5p, -30c-5p) and BMI (miR857, miR168, miR156, miR158).
• In silico or experimental validation of targeting SCN family genes and CLCN5 by identified miRNAs.

Main Results:

• The absence of seizures in SCN1A mutation-positive infants in the first six months suggests a protective role for EGRs from breast milk.
• BML and BMI contain miRNAs and lncRNAs that target SCN family genes and CLCN5, indicating a potential therapeutic mechanism.
• Proposed EGR effects include upregulating SCN1A, down-regulating seizure-associated miRNAs, suppressing methyltransferases, and enhancing NMDA receptor subunits for cognitive improvement.

Conclusions:

• miRNA/lncRNA from BML and bacosides/miRNA from BMI show promise in buffering the effects of SCN1A mutations in aberrant neurons.
• These natural EGRs may sustainably maintain modifier gene effects, offering a novel therapeutic avenue for Dravet Syndrome.
• Further experimental validation is required to strengthen the potential of BML and BMI-derived EGRs as long-term molecular therapeutics for refractory epilepsy.