Editors' ChoiceEpilepsy

MicroRNAs, a Macro Target in Epilepsy?

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Science Translational Medicine  27 Jun 2012:
Vol. 4, Issue 140, pp. 140ec113
DOI: 10.1126/scitranslmed.3004508

Epilepsy characterized by recurrent spontaneous seizures is a disorder that affects millions of children and adults worldwide but is often very difficult to treat. Although our understanding of the underlying pathogenesis of epilepsy has increased, it has proven extremely challenging to develop drugs that decrease seizure frequency.

MicroRNAs are small, endogenously expressed noncoding RNAs that regulate protein expression by binding to target mRNA sequences. In a recent study, Jimenez-Mateos and colleagues discovered that one such microRNA, miR-134, was up-regulated in the temporal lobe of human patients with refractory seizures and in mouse models of epilepsy. To test whether this microRNA had a functional role in epilepsy, they proceeded to knock down miR-134 expression in mice by injecting synthetically engineered strands of RNA (antagomirs) into the brains of mice with seizures.

Using fluorescence-based microscopy, they found that silencing of miR-134 altered the morphology of neurons in the brains of the epileptic mice in a way that would be predicted to decrease their ability to be activated. Moreover, when treated with the antagomirs mice had a decreased frequency of evoked and spontaneous seizures as measured with a micro-electroencephalography machine designed for rodents. Normal brain function, however, appeared to remain intact. In addition, fewer pathological changes that constitute the hallmark of temporal-lobe epilepsy were detected after treatment with the antagomirs. The antiseizure effects of miR-134 blockade were seen for up to 2 months after a single administration of the antagomirs. These data suggest that modulating microRNA expression can control aberrant electrical activity in the brain.

Although miR-134 is a compelling new target for the treatment of epilepsy, further studies are required to develop more suitable methods for inhibiting its function in the brains of human epilepsy patients. Long-term safety and efficacy studies will also be required before microRNAs can have a “macro” clinical impact on the treatment of epilepsy.

E. M. Jimenez-Mateos et al., Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat. Med. 10 June 2012 (10.1038/nm.2834). [Abstract]

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