Neuronal nitric oxide synthase and ischemia-induced neurogenesis.
Nitric oxide (NO) influences infarct size after focal cerebral ischemia and also regulates neurogenesis in the adult brain. These observations suggest that therapeutic approaches to stroke that target NO signaling may provide neuroprotection and also enhance brain repair through cell replacement. However, ischemic injury and neurogenesis are both affected differently depending on which isoform of NO synthase is the source of NO. In addition, ischemia itself stimulates neurogenesis, and ischemia-induced neurogenesis may be regulated differently than neurogenesis in nonischemic brain. To determine how neuronal NO synthase affects ischemia-induced neurogenesis, transient focal cerebral ischemia was produced in wild-type mice and in knockout mice lacking neuronal NO synthase, and BrdU incorporation and doublecortin immunoreactivity were measured in the principal neuroproliferative regions of the adult brain. Knockout of neuronal NO synthase reduced infarct size and increased both basal and ischemia-induced neurogenesis, suggesting that NO from this source is an inhibitory regulator of neurogenesis in the ischemic brain. 7-Nitroindazole, an NO synthase inhibitor that preferentially affects the neuronal isoform, also increased neurogenesis in rats when administered by the intracerebroventricular route. Selective inhibition of neuronal NO synthase may have the potential to both reduce infarct size and enhance neurogenesis in stroke.
Sun
Yunjuan
Y
Buck Institute for Age Research, Novato, California 94945, USA.
Jin
Kunlin
K
Childs
Jocelyn T
JT
Xie
Lin
L
Mao
Xiao Ou
XO
Greenberg
David A
DA
D000818:Animals; D001784:Blood Gas Analysis; D002545:Brain Ischemia / Q000473:pathology*; D001973:Bromodeoxyuridine; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000473:pathology
C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D007191:Indazoles; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D001973:Bromodeoxyuridine; C080122:7-nitroindazole