Normobaric hyperoxia delays and attenuates early nitric oxide production in focal cerebral ischemic rats.
Overproduction of neuronal nitric oxide synthase (nNOS)-derived NO is detrimental during cerebral ischemia. Normobaric hyperoxia (NBO) has been shown to be neuroprotective, extending the therapeutic time window for ischemic stroke, but the mechanism is not fully understood. In the present study, using a rat model of ischemic stroke, we investigated the effect of early NBO treatment on neuronal NO production. Male Sprague-Dawley rats were given normoxia (30% O(2)) or NBO (95% O(2)) during 10, 30, 60 or 90min filament occlusion of the middle cerebral artery. NO(x)(-) (nitrite plus nitrate) and 3-nitrotyrosine were measured in the ischemic cortex. Ischemia caused a rapid increase in the production of NO(x)(-), with a peak at 10min after ischemia onset, then gradually declining to the baseline level at 60min. NBO treatment delayed the NO(x)(-) production peak to 30min and attenuated the total amount of NO(x)(-). Ischemia also increased 3-nitrotyrosine formation, which was significantly reduced by NBO treatment. Inhibition of nNOS by pre-treatment with 7-nitroindazole had similar effect as NBO treatment on NO(x)(-) and 3-nitrotyrosine production, and when combined with NBO, no further reduction in NO production was observed. Furthermore, NBO treatment significantly decreased brain infarct volume. Taken together, our findings demonstrate that delaying and attenuating the early NO release from nNOS may be an important mechanism accounting for NBO's neuroprotection.
Yuan
Zhongrui
Z
College of Pharmacy and Center of Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
Liu
Wenlan
W
Liu
Baoyi
B
Schnell
Aaron
A
Liu
Ke Jian
KJ
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D018496:Hyperoxia / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D020768:Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D009566:Nitrates / Q000378:metabolism; D017942:Nitric Acid / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; C002744:3-nitrotyrosine; D017942:Nitric Acid; D014443:Tyrosine