Neuroprotection by inhaled nitric oxide in a murine stroke model is concentration and duration dependent

Inhaled nitric oxide (iNO) has been shown to reduce ischemia/reperfusion (I/R) injury in several different organ systems including the brain. We investigated whether iNO was neuroprotective in a mouse model of transient focal ischemia. Male Swiss Webster mice underwent middle cerebral artery occlusion for 1 h followed by reperfusion for 47 h. Mice were divided into 5 concentration groups and administered nitric oxide (NO) at either 10, 20, 40, 60 or 80 ppm. Each of the 5 concentration groups was subdivided into 4 duration groups which were treated with iNO for 5, 8, 16 or 24 h beginning immediately after artery occlusion. Results showed both concentration and duration determined efficacy At 10 ppm only the 24 hr duration group exhibited reduced infarct volume while at 20, 40 and 60 ppm only 8 and 16 h of exposure led to smaller infarctions. At these concentrations the dose response curves were strongly U shaped indicating a loss of benefit at long durations. At 80 ppm, reduction in infarct volume was not observed at any duration. Additional experiments showed that 60ppm iNO could be transported from lung to brain and that iNO administered for 8 h improved recovery from subarachnoid hemorrhage and reduced the inflammatory response accompanying ischemic stroke. Enhanced blood flow during reperfusion may be an important mediator of these effects. (C) 2013 Elsevier B.V. All rights reserved.