Plasma microRNAs as prognostic biomarkers for development of severe epilepsy after experimental traumatic brain injury—EpiBioS4Rx Project 1 study

Abstract

Objective: To test a hypothesis that acutely regulated plasma microRNAs (miRNAs) can serve as prognostic biomarkers for the development of post-traumatic epilepsy (PTE). Methods: Adult male Sprague–Dawley rats (n = 245) were randomized to lateral fluid-percussion–induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, United States). Video-electroencephalography (vEEG) was performed on the seventh post-injury month to detect spontaneous seizures. Tail vein plasma collected 48 h after TBI for miRNA analysis was available from 209 vEEG monitored animals (45 sham, 164 TBI [32 with epilepsy]). Based on small RNA sequencing and previous data, the seven most promising brain enriched miRNAs (miR-183-5p, miR-323-3p, miR-434-3p, miR-9a-3p, miR-124-3p, miR-132-3p, and miR-212-3p) were validated by droplet digital polymerase chain reaction (ddPCR). Results: All seven plasma miRNAs differentiated between TBI and sham-operated rats. None of the seven miRNAs differentiated TBI rats that did and did not develop epilepsy (p >.05), or rats with ≥3 vs <3 seizures in a month (p >.05). However, miR-212-3p differentiated rats that developed epilepsy with seizure clusters (i.e., ≥3 seizures within 24 h) from those without seizure clusters (.34 ±.14 vs.60 ±.34, adj. p