Reducing Secondary Traumatic Brain Injury by Early Remote Ischemic Pre-Conditioning
Abstract
The objective of this proposal is to determine if remote ischemic pre-conditioning, a process in which normal tissues are subjected to brief cycles of non-lethal ischemia and reperfusion, done early after prima1y traumatic brain injmy can reduce seconda1y traumatic brain injury and improve clinical outcomes. Remote Ischemic Preconditioning (RIPC) is a process in which normal tissues are subjected to short cycles ofischemia and reperfusion which reduces an ischemic inju1y at a remotely injured site. It is thought to work by releasing endogenous anti-inflammatory mediators rende1ing global protection to the body against subsequent ischemic insults and has been shown to improve outcomes after myocardial infarction, sepsis, transplantation, re-implantation and elective neurosurgical surgery. We hypothesized that TBI patients may benefit from the implementation of RIC. Aim l. To examine markers of damage to neurons and astrocytes. Circulating levels ofSlOO-B, neuron specific enolase (NSE) and Glial fibrilla1y acidic protein (GF AP). Aim 2. To assess cognitive perfomrnnce and motor coordination using Novel object recognition and rotarod test. Aim 3. To evaluate brain samples for neuronal injury and astrogliosis using Light microscopy and immunohistochemical techniques. Methods: 100 male C57BL mice were subjected to a cortical controlled impact injury. Two hours after TBI, animals were allocated to RIC (n = 10) or Sham (n = 10) at 3 early time points (2, 6 and 24 hours) and 2 late time points (48-120 hours) post-intervention (RIC or Sham). RIC was performed for 6 cycles ofischemia and reperfusion by clamping the femoral artery. Circulating levels of S100-B, neuron specific enolase (NSE) and Glial fibrillary acidic protein (GFAP) were serially measured as markers of damage to neurons and astrocytes at these 5 time points. Similarly, another 24 animals were subjected to a cortical controlled impact injury. Two hours after TBI, animals were allocated to RIC (n = 12) or Sham (n = 12) then assessed at 24-, 48-, 72-, 96- and 120- h post-intervention (RIC or Sham) for cognitive petformance and motor coordination using novel object recognition and rotarod tests, respectively. Animals were sacrificed at day 5 and brain sections were stained by Hematoxylin and eosin (H&E) and analyzed for neuronal injury (development of cytoplasmic eosinophilia, shrinkage of the perikaryon) at the cortex and Hippocampus C1. Results: There was no significant difference in systemic neuronal markers between RIC and Sham animals. Se1um GFAP trended down while serum NSE and S100-B trended up in both RIC and Sham animals. RIC animals had significantly higher recognition index than Sham post-intervention. Latency to fall was higher in RIC animals compared to Sham animals at all time points post-intervention. The RIC group demonstrated significantly improved cognitive function and motor coordination compared to the Sham group. More areas of neuronal degeneration were observed in Hippocampus Cl in the Sham group compared to RIC group. Conclusion: Remote ischemic conditioning post-injmy results in quicker recovery of cognitive functions and improved balance and motor coordination in a mouse model of traumatic brain injmy. Less neuronal degeneration was observed with RIC despite no significant changes in systemic biomarkers of brain injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 12, 2017
- Source ID
- W911NF1510093
Entities
Organizations
- Army Contracting Command
- Office of the Secretary of Defense
- University of Arizona