Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model

Abstract

Object In traumatic brain injury (TBI) patients, hypothermia therapy has not shown efficacy in multicenter clinical trials. With the post-hoc data from the latest clinical trial (NABIS:H II), we hypothesized that hypothermia may be beneficial in the rat acute subdural hematoma (ASDH) model by blunting the effects of ischemic/ reperfusional (I/R) injury. The major aim of our study was to test the efficacy of temperature management in reducing brain damage after ASDH. Methods Rats were induced with ASDH and placed into (1) Normothermia group (37°C) (2) Early hypothermia group; head and body temperature reduced to 33°C at 30 minutes prior to craniotomy (3) Late hypothermia group; temperature was lowered to 33°C at 30 minutes after decompression (4) Sham group; no ASDH and underwent only craniotomy with normothermia. To assess of neuronal and glial cell damage, we analyzed microdialysate (MD ; using 100kD probe) concentrations of: glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1). Fluoro-Jade B (FJB) positive neurons and injury volume with 2,3,5-triphenyltetrazolium chloride (TTC) staining were also measured. Results In the early phase of reperfusion (30min- 2.5 hrs after decompression), extracellular UCH-L1 in the early hypothermia group was significantly lower than in the normothermia. (Early; 4.9±1.0 ng/dl, Late; 35.2±12.1 ng/dl, Normo; 50.20± 28.3 ng/dl, Sham; 3.1±1.3 ng/dl, Early vs Normo; p < 0.01, Sham vs Normo; p < 0.01, analyzed with ANOVA followed by a post-hoc Bonferroni’s test ). In the late phase of reperfusion (> 2.5hrs after decompression), extracellular GFAP in the early hypothermia group was also lower than in the normothermia and late hypothermia groups (Early; 5.5±2.9 ng/dl, Late; 7.4±3.4 ng/dl, Normo; 15.3±8.4 ng/dl, Sham; 3.3±1.0 ng/dl, Normo vs Sham; p < 0.01). The number of FJB positive cells in early hypothermia group was significantly smaller than in normothermia group (Normo vs Early: 774,588 ± 162,173 vs 180,903 ± 42,212, p<0.05). Also, the injury area and volume were smaller in the early hypothermia group in which hypothermia was induced before craniotomy and cerebral reperfusion (115.2±15.4 mm3 in early hypothermia group, 344.7±29.1 mm3 in late hypothermia group, 311.2±79.2 mm3 in Normothermia group p<0.05). Conclusion In conclusion, the data suggests early, preoperatively induced hypothermia could mediate the reduction of neuronal and glial damage in reperfusional phase of ischemic/reperfusional brain injury.

Military Personnel with Chronic Symptoms Following Blast Traumatic Brain Injury Have Differential Expression of Neuronal Recovery and Epidermal Growth Factor Receptor Genes

“…Pre-clinical models also link blast to an increase in UCH-L1 in blood and CSF, with CSF elevations lasting for 14 days, as well as increases in other putative biomarkers of brain injury glial fibrillary acid protein, and neuron-specific enolase ( 34 ). Minimization of the ubiquitin pathway following a blast-TBI, by inducing hypothermic conditions, resulted in less UCH-L1 activity following blunt force and a reduction of neuronal and glial damage ( 35 ). Therefore, additional studies are needed to determine how the ubiquitin pathway relates to neuronal damage following blast, and if it may be a pharmacological target to promote neuronal recovery from blast.…”

Strategies for CNS repair following TBI

“…This subset analysis corresponds with the results from recent experiments in a rodent model of subdural hemorrhage. These models have shown that preoperative hypothermia is associated with reduced damage to neurons and glial cells (Yokobori et al, 2013a;Yokobori et al, 2013b). In light of these conflicting results, therapeutic hypothermia remains an area of active clinical investigation with at least 3 trials ongoing: POLAR-RCT (NCT00987688), the HOPES Trial (NCT02064959), and Eurotherm3235 (Andrews et al, 2013).…”

Fundamental research progress of mild hypothermia in cerebral protection

“…Therefore, the time window for mild hypothermia beginning should be actively sought (Tissier et al 2011). One research found that pre-operation hypothermia could reduce the damage of neuron and glia in the reperfusion phase of ischemia/reperfusion brain injury (Yokobori et al 2013). Therefore, hypothermia should be initiated as soon as possible to achieve its optimal beneficial effect.…”