Therapeutic hypothermia (TH) improves neurologic outcomes after CNS injury. Preclinical studies show that mild cooling to ~33C has beneficial effects on the injured brain which involves multiple mechanisms including (but not limited to): fever reduction, decreasing metabolic demand/ATP consumption, decreasing intracellular mediators of apoptosis, and increasing pro-survival proteins. In contrast, TH can also increase the risk of adverse complications like infection, ion disturbances, hyperglycemia, and insulin resistance ? which may increase mortality or worsen brain injury. TH surprisingly has failed to translate in traumatic brain injury (TBI) in either children or adults. Recent clinical trials were done to compare if neurological outcomes were better in cardiac arrest patients treated with mild TH to 33C vs. fever prevention using targeted temperature management (TTM) to ~36C. No difference in neurological outcome was observed - indicating that TH and TTM had similar therapeutic efficacy. Inhibition of fever in both treatment groups may explain those surprising findings; fever by as little as 1-2C is well known to dramatically worsen neurologic outcomes. Given that both temperatures provided similar benefits, and because the application of TTM is associated with fewer adverse side effects than TH, TTM may be the safest therapeutic option for temperature management. Conversely, a key limitation of TTM is that it is not thought to activate additional neuroprotective mechanisms (as does TH). The next advance in temperature management therapy may be to discover drugs which make TTM more neuroprotective (Concept 1), or alternatively (Concept 2) drugs which lessen the systemic side effects of neuroprotective TH. This R21 will test if fibroblast growth factor 21 (FGF21) augments TTM/TH induced neuroprotection in a rat model of pediatric TBI, in part, by upregulating the highly neuroprotective cold- shock protein RNA binding motif 3 (RBM3).
PROJECT NARRITIVE Acute brain injury is a leading cause of death and disability. Therapeutic hypothermia (TH) is among the few therapies proven to reduce neurologic impairment in surviving patients. TH is not without risks and can increase adverse complications. Recent clinical trials suggest that fever prevention using targeted temperature management (TTM) to 36C is equally effective as TH on neurologic outcomes in brain injured patients. Our proposal will test if a novel therapy (i.e. fibroblast growth factor 21; FGF21) activates a novel and highly neuroprotective signaling mechanism in vivo (i.e. cold-shock protein RNA binding motif 3; RBM3), as a method to markedly enhance the neurologic benefits of TTM and TH cooling after a brain injury.
| Jackson, Travis C; Kotermanski, Shawn E; Jackson, Edwin K et al. (2018) BrainPhys® increases neurofilament levels in CNS cultures, and facilitates investigation of axonal damage after a mechanical stretch-injury in vitro. Exp Neurol 300:232-246 |
| Jackson, Travis C; Kotermanski, Shawn E; Kochanek, Patrick M (2018) Infants Uniquely Express High Levels of RBM3 and Other Cold-Adaptive Neuroprotectant Proteins in the Human Brain. Dev Neurosci 40:325-336 |
| Kochanek, Patrick M; Jackson, Travis C (2017) Therapeutic Hypothermia and Targeted Temperature Management With or Without the ""Cold Stress"" Response. Ther Hypothermia Temp Manag 7:134-136 |
