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. Given limited understanding of the transcriptional changes associated with its pathophysiological cascades, we studied formalin fixed paraffin embedded (FFPE) tissues from the frontal cortex (FC) and the hippocampus + amygdala (HA) 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 5 temporal patterns (Early, Transient, Persistent, Intensified, Delayed, or Late), and 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 (20mg/kg/day) infused for 1 day, (beginning at 6 hours after injury) accelerated 466 DEGs in the FC and 2794 DEGs in the HA, such that the CsA treated transcriptional profile were associated with neurorecovery. Overall, our data reveals the effects of anatomic region and elapsed time on gene expression post-mTBI and motivates future studies of CsA treatment. To investigate temporal transcriptional profiles and the neuroprotective effect of CsA treatment, we utilized piglet FFPE brain tissue from sham/naïve animals, animals sacrificed at 1 day, 1 week, and 30 hours following CsA treatment. All samples underwent RNA-sequencing and gene expression profiling was conducted on samples that passed library prep (i.e. 40 subjects).