title: Mild therapeutic hypothermia does not reduce thrombin-induced brain injury.
abstract: Secondary neurodegeneration occurs hours to days after an intracerebral hemorrhage (ICH). Thrombin, a protease important in clotting, is one of the causes of this injury. Presently, we evaluated whether hypothermia mitigates thrombin-induced cerebral edema, cell death, and behavioral impairment. Rats were given a striatal infusion of thrombin, which models thrombin-mediated injury occurring after ICH, followed an hour later by whole-body cooling (33°C), local brain hypothermia (∼ 33°C), or normothermia. Thrombin caused significant edema at 24 hours (∼ 5% increase in water) that was not mitigated by whole-body or brain-selective cooling. Other rats were infused with thrombin and systemically cooled for 72 hours. At a 14-day survival they had similar walking impairments and brain tissue loss (∼ 45 mm(3)) as normothermic rats. However, cooled animals had significantly more degenerating neurons in the peri-lesion zone (p=0.035), which were rare in normothermic rats. Thus, it appears that some cell death was increased or delayed by hypothermia. In summary, we did not find that hypothermia reduced thrombin-induced neurotoxicity. This suggests that cooling does not effectively target thrombin-mediated secondary degeneration after ICH, which may partly explain why cooling is often not robustly neuroprotective in rodent ICH studies. These findings also indicate that therapeutic hypothermia could be improved by the addition of drugs to minimize thrombin toxicity.
authors.affiliation: 1 Neuroscience and Mental Health Institute, University of Alberta , Edmonton, Canada .
authors.forename: Shannon
authors.initials: S
authors.lastname: Wowk
authors.forename: Yonglie
authors.initials: Y
authors.lastname: Ma
authors.forename: Frederick
authors.initials: F
authors.lastname: Colbourne
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000628:therapy*; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000008:administration & dosage*
chemical_list: D013917:Thrombin