A detrimental role for nitric oxide synthase-2 in the pathology resulting from acute cerebral injury.
Nitric oxide (NO) synthesized from the inducible isoform of nitric oxide synthase (NOS-2) has been suggested to play both beneficial and deleterious roles in various neuropathologies. To define the role of nitric oxide in traumatic brain injury, we subjected male mice lacking a functional NOS-2 gene (NOS-2-/-) and their wild-type littermates (NOS-2+/+) to mild or severe aseptic cryogenic cerebral injury. Expression of NOS-2 mRNA and protein was observed in NOS-2+/+ animals following injury. Lesion volume (as measured by histology and brain imaging) and neurological outcome (using motor and cognitive behavioral paradigms) were assessed at various times after injury. While magnetic resonance imaging revealed the extent of edema of the 2 genotypes to be similar, histology showed a reduced (32%) lesion volume in severely injured NOS-2-/- compared with NOS-2+/+ mice. In addition, NOS-2-/- mice showed significant improvements in both contralateral sensorimotor deficits (grid test: p = 0.011) and cognitive function (Morris water maze: p = 0.009) after severe injury compared to their wild-type littermates. This indicates that lesion volume is reduced and neurological recovery is improved after acute traumatic injury in mice lacking a functional NOS-2 gene, and strongly suggests that the post-trauma production of NO from this source contributes to neuropathology.
Jones
N C
NC
Institute of Cell Signalling, University of Nottingham, Nottingham, United Kingdom.
Constantin
D
D
Gibson
C L
CL
Prior
M J W
MJ
Morris
P G
PG
Marsden
C A
CA
Murphy
S
S
D000208:Acute Disease; D000818:Animals; D001929:Brain Edema / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001930:Brain Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009069:Movement Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics
D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II