Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice.
Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1. 5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS(-/-)) were compared with wild-type (iNOS(+/+)) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS(+/+) and iNOS(-/-) mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS(-/-) mice showed markedly worse performance in the MWM task than iNOS(+/+) mice. A beneficial role for iNOS in TBI is supported.
Sinz
E H
EH
Department of Anesthesiology and Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pennsylvania 15260, USA.
Kochanek
P M
PM
Dixon
C E
CE
Clark
R S
RS
Carcillo
J A
JA
Schiding
J K
JK
Chen
M
M
Wisniewski
S R
SR
Carlos
T M
TM
Williams
D
D
DeKosky
S T
ST
Watkins
S C
SC
Marion
D W
DW
Billiar
T R
TR
D000818:Animals; D001925:Brain Damage, Chronic / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D000860:Hypoxia / Q000201:enzymology / Q000473:pathology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D011833:Radiation Injuries, Experimental / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014916:Whole-Body Irradiation; D014949:Wounds, Nonpenetrating / Q000201:enzymology / Q000473:pathology
D004791:Enzyme Inhibitors; D006146:Guanidines; C090663:N(6)-(1-iminoethyl)lysine; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D008239:Lysine; C004479:pimagedine