Evaluation of the prognostic potential of MicroRNAs in the development of epilepsy after traumatic brain injury

Abstract

MicroRNAs (miRNAs) are small molecules of endogenous regulatory, non-coding RNAs that provide an epigenetic mechanism for regulating protein expression levels of target genes. miRNAs are considered as serum diagnostic biomarkers for various diseases due to their stability and detection in minute amounts. These small regulators can be found in fluids such as blood, serum, saliva, urine, and cerebrospinal fluid. More than 2000 miRNAs have been identified and more than 50% of these are expressed in the brain. MiRNAs are related to many brain functions that are relevant to epilepsy and epileptogenesis, including cell death, neurogenesis, and synaptic plasticity (Karnati et al., 2015). Studies of expression profiling of miRNAs present in blood as a result of different types of acute brain insults that can potentially generate acquired epilepsy (SE, stroke, infection, and trauma), show that each insult produces unique miRNA expression responses, but, a subset of these miRNAs are shared across different types of brain injuries, suggesting a set of common miRNAs that may represent biomarkers of epileptogenic injury (Henshall et al., 2015). Specifically in animal models of epilepsy, more than 20 miRNAs have been found to be differentially expressed in brain tissues of animals, and importantly, several of them also show consistent changes in resected tissue from patients with intractable epilepsy (Henshall et al., 2015; Korotkov et al., 2017). In addition to patients with epilepsy, miRNAs are also found altered in patients with moderate and severe TBI (Redell et al., 2010; Bhomia et al., 2016). Studies with in vivo manipulation of individual miRNAs show that they play functional roles in controlling inflammation, cell death, and hyperexcitability (Henshall et al., 2015), supporting the idea that they may have a pathogenic role in acquired epilepsies (Henshall et al., 2016, Cattani et al., 2016; Simonato, 2018). In the present project we seek to identify patterns of changes in the levels of circulating miRNAs and carried by extracellular vesicles after TBI that may be related to the development of EPT and have possible therapeutic value. Exosomes are small extracellular vesicles of approximately 50 to 100 nm in diameter formed by a lipid bilayer and differ from other vesicles released by cells by size, density, lipid composition, and the presence of specific proteins in the lipid bilayer. They can be released from virtually any cell type, including neural cells, and their release is related to both physiological processes and pathological conditions. These vesicles have been shown to show promise by recent discovery of mediator function in cell communication, acting as "deliverers" of proteins, mRNAs and miRNAs to recipient cells. Therefore, miRNAs carried by exosomes may be potential biomarkers.