Endothelin-1 is upregulated after traumatic brain injury: a cross-species, cross-model analysis

Objectives: This work was designed to compare levels of endothelin-1 following brain injury in both rat and porcine models of head injury. In a broader sense, this work also determines the feasibility of testing traumatic brain injury-related phenomenology across species and models. Methods: Male Sprague-Dawley rats (400-450 g) were subjected to traumatic brain injury using a weight acceleration impact injury device (n=5 per group). Following impact, cerebrospinal fluid was collected for enzyme-linked immunosorbent assay analysis of endothelin-1 concentration using a standard endothelin-1 detection kit at 4 hours, 24 hours, 48 hours, and 7 days post-traumatic brain injury. Sham operated animals (n=5) were used as controls. In another set of experiments, traumatic brain injury was induced in newborn and juvenile pigs (n=6 per group) using a lateral fluid percussion model of brain injury. Cerebrospinal fluid was collected at 4 hours, 8 hours, 72 hours, and 7 days post-injury and endothelin-1 levels were measured using a radiolabeled kit. Results: Endothelin-1 levels rapidly increased from similar to 35 in sham operated animals to over 200 pg/g tissue 4 hours post-impact in both rat cortex and hippocampus. This elevation was sustained through 48 hours post-impact. By 7 days post-injury, endothelin-1 levels returned to normal, control concentrations. This trend was consistent with the porcine model, being more pronounced in newborn versus juvenile pigs. Conclusion: These results show that endothelin-1 peptide concentration elevation is a consistent finding between rat and pig and between weight acceleration and fluid percussion models of traumatic brain injury. This suggests that endothelin-1 elevation is not only a conserved phenomenon in different models of traumatic brain injury, but that it is a likely target for understanding the observed enhanced vascular response to traumatic brain injury and ultimately developing strategies to improve outcome following traumatic brain injury.