Targeting microRNA-134 for seizure control and disease modification in epilepsy

Abstract

MicroRNA-134 is a brain-enriched small noncoding RNA that has been implicated in diverse neuronal functions, including regulating network excitability. Increased expression of microRNA-134 has been reported in several experimental epilepsy models and in resected brain tissue from temporal lobe epilepsy patients. Rodent studies have demonstrated that reducing microRNA-134 expression in the brain using antisense oligonucleotides can increase seizure thresholds and attenuate status epilepticus. Critically, inhibition of microRNA-134 after status epilepticus can potently reduce the occurrence of spontaneous recurrent seizures. Altered plasma levels of microRNA-134 have been reported in epilepsy patients, suggesting microRNA-134 may have diagnostic value as a biomarker. This review summarises findings on the cellular functions of microRNA-134, as well as the preclinical evidence supporting anti-seizure and disease-modifying effects of targeting microRNA-134 in epilepsy. Finally, we draw attention to unanswered questions and some of the challenges and opportunities involved in preclinical development of a microRNA-based oligonucleotide treatment for epilepsy.

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

“…Thus, although a series of micro-RNAs have been shown to associate with human TLE (Miller-Delaney et al, 2015), the studied tissue had been surgically resected from people with drug resistance, and cause and effect (for either disease susceptibility or drug resistance) could not be distinguished. In animal models, manipulation of specific microRNAs can Drug-Resistant Epilepsy influence seizures and disease (Morris et al, 2019), though some data are less supportive (Haenisch et al, 2016); however, whether this would be the case in human epilepsy, and specifically whether this approach would counter drug resistance, remains unknown.…”

Anti-Epileptogenic Effects of Antiepileptic Drugs

“…However, the drug has been found effective in pediatric epilepsy [59,60]. Recent data indicate that antisense oligonucleotids reducing SE-produced expression of microRNA-134 have been effective in attenuation the spontaneous seizure activity [61]. In addition to celecoxib, some other cyclooxygenase inhibitors (for instance, SC58236) were tried as anti-epileptogenic agents after electrically-induced SE through electrodes placed in the angular bundle in rats.…”

Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

“…The study of the epigenomic contribution to drug resistance in epilepsy is an extremely complex task, in which it is difficult to separate cause from effect and significance from epiphenomena [60,79]. Manipulations with specific microRNAs can affect convulsions and the course of disease in laboratory animals but there is very little data on humans, especially without genetic abnormalities [80]. A study of 75 people from northern China, 25 of whom had carbamazepine (CBZ)-resistant epilepsy, showed a significant difference in methylation levels in the promoter of the epoxide hydrolase 1 gene EPHX1 between them, CBZ-sensitive patients and controls.…”