March 25, 2021

CURE Epilepsy Discovery: A Novel Molecule as a Biomarker of Epilepsy

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Gary Brennan and colleagues used three different, well-established rodent models of acquired epilepsy to identify biomarkers for both diagnosing active epilepsy and for predicting who might develop epilepsy after a brain injury.
  • The team found that a family of small molecules known as microRNAs (miRNAs)[1], which are important in regulating gene expression and brain activity, were altered in rodent models of acquired epilepsy.
  • Three of the five identified miRNAs were also present in blood samples taken from epilepsy patients, thereby validating their relevance to human epilepsy.
  • Administration of a molecule known as Ant-134, which has been previously shown to reduce seizure frequency in different animal models, affected the levels of three of the five miRNAs in rodent models of acquired epilepsy in the current study.
  • These preliminary data suggest that circulating miRNAs may represent biomarkers that can accurately diagnose epilepsy and predict who may develop it after a brain injury. Additional steps to validate these miRNAs as biomarkers of acquired epilepsy are needed.

Deep Dive:

Epilepsy is often “acquired” by injuries to the brain such as those resulting from a stroke, head trauma, or infection. There is currently no way of reliably predicting who will develop epilepsy following these types of injuries [2]. Thus, it would be valuable to have a stable, readily accessible substance (in the blood, for example) to assist with diagnosis, treatment, and epilepsy prediction following a head injury for people at risk. MicroRNAs (miRNAs), small molecules that have been implicated in the development of epilepsy [3], may make ideal biomarkers due to their relatively high concentrations in the blood. CURE Epilepsy Taking Flight Award grantee Dr. Brennan investigated whether miRNAs might be used as biomarkers of acquired epilepsy.

Dr. Brennan and his colleagues employed three different rodent models of acquired epilepsy to evaluate the feasibility of using miRNAs as biomarkers for the development of epilepsy [4]. The researchers first collected blood from all rodents to establish baseline levels of the different miRNAs. They subsequently sampled blood several times prior to the first seizure and also on the day of the first spontaneous seizure, which was indicative of the actual onset of epilepsy.

The researchers found that blood from rodents with epilepsy had several unique miRNAs, either newly-emerged or whose levels had changed during epileptogenesis –the process by which an initial “insult” or injury to the brain leads to seizures and epilepsy–and into the chronic epilepsy stage. Based on consistency among the three rodent models and previous associations with epilepsy, the researchers chose five of these miRNAs as a focus for the next steps of their work. Importantly, they found that three of the five miRNAs were also found in people with epilepsy.

Dr. Brennan also found that levels of three of the five miRNAs were affected by a potential new therapy for epilepsy called Ant-134. Anti-134 is a molecule that specifically targets a different miRNA (miRNA-134), distinct from the five miRNAs that were the focus of Dr. Brennan’s study. Anti-134 has been shown to reduce seizures in several different rodent models of epilepsy [5]. Dr. Brennan’s finding supports the idea that specific miRNAs may be useful for predicting the likelihood of developing an acquired epilepsy as well as potential indicators of treatment responsiveness.

These exciting data reveal a novel mechanism of epilepsy prediction, diagnosis, and treatment that may one day be studied in clinical trials to determine its ability to identify individuals who have suffered a brain injury that are likely to develop epilepsy.

Dr. Gary Brennan

Dr. Brennan performed his work while in the laboratory of Dr. David Henshall at the Royal College of Surgeons in Ireland. He collaborated with multiple colleagues, both in Dr. Henshall’s lab and from specialist labs across Europe.

Dr. Brennan has received additional support from the Science Foundation Ireland and is a funded investigator in the FutureNeuro Research Centre. His research group is based in the School of Biomolecular and Biomedical Science at University College Dublin.


Literature Cited
[1] miRNA are (a relatively newly discovered form of ribonucleic acid (RNA) and) distinct from other forms of ribonucleic acids (RNA) like mRNA or tRNA that serve different biological functions.
[2] Löscher, W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2020; 167: 107605.
[3] Henshall, D.C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 2016; 15(3): 1368-1376.
[4] Brennan, G.P. et al. Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy. Neurobiol. Dis. 2020; 144: 105048.
[5] Morris, G., Reschke, C.R., and Henshall, D.C. Targeting microRNA-134 for seizure control and disease modification in epilepsy. EbioMedicine 2019; 45: 646-654.

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