Effects of post-injury hypothermia and nerve growth factor infusion on antioxidant enzyme activity in the rat: implications for clinical therapies.
The pathological sequelae of traumatic brain injury (TBI) include increased oxidative stress due to the production of reactive oxygen species (ROS). Regulation of ROS levels following TBI is determined primarily by antioxidant enzyme activity that in turn can be influenced by nerve growth factor (NGF). Hypothermia is one of the current therapies designed to combat the deleterious effects of TBI. However, it has been shown to suppress post-trauma increases in NGF levels in rat brain. The present study sought to determine whether post-injury hypothermia also impairs the antioxidant response to injury, and if such an effect could be reversed by infusion of exogenous NGF. We employed a lateral controlled cortical impact injury model in rat, followed by moderate hypothermia treatment with supplemental intracerebroventricular infusion of NGF or vehicle. The time course of changes in post-injury/intervention levels of NGF and activity of three major enzymes responsible for ROS scavenging, catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), was determined in the hippocampus. Relative to levels in injured, normothermic animals, hypothermia treatment not only suppressed NGF levels, but also attenuated CAT and GPx activity, and increased SOD activity. Infusion of NGF in injured, hypothermia-treated animals was ineffective in restoring hippocampal antioxidant enzymes activity to levels produced after injury under normothermic conditions, although it was able to increase septal cholinergic (choline acetyltransferase) enzyme activity. These results have implications for clinical treatment of TBI, demonstrating that moderate hypothermia suppresses NGF and the antioxidant response after TBI; the latter cannot be countered by exogenous NGF administration.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. DeKoskyST@upmc.edu
Steven T
ST
DeKosky
Eric E
EE
Abrahamson
Kevin M
KM
Taffe
C Edward
CE
Dixon
Patrick M
PM
Kochanek
Milos D
MD
Ikonomovic
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000628:therapy*; D002374:Catalase / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004798:Enzymes / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007036:Hypothermia, Induced / Q000009:adverse effects; D007276:Injections, Intraventricular; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D004798:Enzymes; D020932:Nerve Growth Factor; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase