Delayed neural damage is induced by iNOS-expressing microglia in a brain injury model.
Most CNS diseases begin with inflammation with subsequent neural damage eventually occurring; however, the process leading from the onset of inflammation to neural damage remains obscure. We used an artificial brain injury mouse model and examined how neural damage occurred in the brain parenchyma. The damaged area in each mouse was clearly observed by magnetic resonance imaging (MRI), and the progression of damage was observed to occur in a biphasic manner (acute damage, within 1 week; delayed damage, after 2 weeks). We found that the delayed neural damage was absent in iNOS-deficient mice (iNOS-KO mice). Then, we analyzed brain tissues and determined that delayed neural damage was accompanied by an increase in the levels of NO end products and iNOS expression, with accumulation of iNOS-expressing microglia around the injured area. In addition, the expression of IL-1beta mRNA was increased in areas affected by acute damage, but not in those affected by delayed damage. These findings suggest that delayed neural damage might arise from NO production by iNOS-expressing activated microglia and that such activated microglia might become a therapeutic target for many CNS diseases.
Ono
Kenji
K
Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601, Japan. k_ono@riem.nagoya-u.ac.jp <k_ono@riem.nagoya-u.ac.jp>
Suzuki
Hiromi
H
Sawada
Makoto
M
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000431:Ethanol; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology*; D009474:Neurons / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis
D053583:Interleukin-1beta; D012333:RNA, Messenger; D009569:Nitric Oxide; D000431:Ethanol; D052247:Nitric Oxide Synthase Type II