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The molecular effect of mild epileptic seizures on the brain is poorly understood. A team of neuroscientists lead by Carlos Fitzsimons (SILS-UvA) have discovered how to revert effects of small RNA molecules present after a seizure, thereby protecting affected stem cells in the brain. The research was published in the journal 'Frontiers in Molecular Neuroscience'.

Brain

Effects of epileptic seizures on the brain

Epilepsy patients can experience convulsive seizures. It is known that the hippocampus, an important part of the brain involved with memory storage and spatial memory, is affected by these seizures via changes in the available neural stem cell pool. However, part of epilepsy patients suffer from milder, non-convulsive seizures. The exact effects of these milder seizures on neural stem cells was poorly characterized thus far. Fitszimons and his team set out to learn more about the effects of these milder seizures, hoping to find promising insights for therapeutic interventions.

Keeping neural stem cells alive

Neural stem cells are essential as a source for adult neurogenesis in the hippocampus, a process that keeps the brain functioning and healthy. Therefore it is important to understand what effect epilepsy seizures have on these neural stem cells. It is known that the fate of neural stem cells is regulated by the expression of several genes, and these genes are in their turn regulated by a variety of biological processes, including small molecules called microRNAs.

Multiple of these microRNAs can work together to reach highly specific effects, for example blocking a big set of genes to control the behaviour of neural stem cells. Fitszimons and team characterized the effect of two microRNAs, miRNA-124 and -137, that are often detected after seizures. The microRNAs are responsible for depleting the neural stem cell population, so it would be promising to block these microRNAs. This was made possible by specifically designed anti-microRNA oligonucleotides. By using these anti-microRNA oligonucleotides, the effect of miRNA-124 and -137 was blocked, thereby reverting the loss of neural stem cells after non-convulsive seizures. A highly promising result with potential for future seizure therapy.

The promise of RNA interference therapy

Though promising, anti-microRNA molecules are not regularly used in the clinic yet. This is due to the complexity of the technique, called RNA interference. The mechanism of RNA interference was already discovered in 1998, but due to the challenging complexity, only recently the first RNA interference-based drug ‘Patisiran’ was approved by the US FDA. This has inspired a rebirth in therapeutic applications for RNA interference. The study by Fitszimons and team support the promise for a future application for RNA interference-based therapies for epilepsy syndromes.

Publication

Bielefeld P. et al, Co-administration of Anti microRNA-124 and -137 Oligonucleotides Prevents Hippocampal Neural Stem Cell Loss Upon Non-convulsive Seizures, Frontiers in Molecular Neuroscience, 19 February 2019, doi: https://doi.org/10.3389/fnmol.2019.00031