Cyclosporine A Accelerates Neurorecovery Transcriptional Trajectory in a Swine Model of Diffuse Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is a leading cause of morbidity in children with both short- and long-term neurological, cognitive, cerebrovascular, and emotional deficits. These deficits have been attributed to ongoing pathophysiological cascades that occur acutely and persist post-injury. Given our limited understanding of the transcriptional changes associated with these pathophysiological cascades, we studied formalin-fixed paraffin-embedded (FFPE) tissues from the frontal cortex (FC) and the hippocampus + amygdala (H&A) regions of swine (N = 40) after a sagittal rapid non-impact head rotation (RNR). We then sequenced RNA to define transcriptional changes at 1 day and 1 week after injury and investigated the protective influence of cyclosporine A (CsA) treatment. Differentially expressed genes (DEGs) were classified into five temporal patterns (Early, Transient, Persistent, Intensified, Delayed, or Late). DEGs were more abundant at 1 week than 1 day. Shared significant gene ontology annotations in both regions included terms associated with neuronal distress at 1 day and neurorecovery at 1 week. CsA (20 mg/kg/day) infused for 1 day (beginning at 6 h after injury) accelerated 466 DEGs in the FC and 2794 DEGs in the H&A, such that the CsA-treated transcriptional profile was associated with neurorecovery. Overall, our data reveal the effects of anatomic region and elapsed time on gene expression post-mTBI and motivate future studies of CsA treatment.