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MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control. | LitMetric

AI Article Synopsis

  • There is a pressing need for new treatments for epilepsy that does not respond to current medications, particularly since sodium channel blockers may not work for all genetic forms of epilepsy.
  • Researchers conducted a study that identified a specific microRNA, miR-335-5p, which plays a key role in regulating voltage-gated sodium channels, potentially affecting neuronal excitability and seizure control.
  • Modulating miR-335-5p showed promising results, with inhibiting it increasing seizure susceptibility, while its overexpression reduced seizure severity, suggesting it could be a target for new therapeutic strategies for treatment-resistant epilepsy.

Article Abstract

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of , , and in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and , and expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10372546PMC
http://dx.doi.org/10.1073/pnas.2216658120DOI Listing

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