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A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology
Published on: March 17, 2016
Neuroprotection by inhaled nitric oxide in a murine stroke model is concentration and duration dependent
Yong-Sheng Li1, Benjamin Shemmer, Eric Stone
1Department of Neurology, New York University School of Medicine, 550 1st Avenue New York, NY 10016, USA.
Abstract:
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 24hr 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 60 ppm iNO could be transported from lung to brain and that iNO administered for 8h 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.
Insights
Inhaled nitric oxide (iNO) shows neuroprotective effects against stroke in mice, with optimal benefits seen at specific concentrations and durations. The study highlights iNO
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Research
Background:
- Ischemia/reperfusion (I/R) injury affects multiple organs, including the brain.
- Inhaled nitric oxide (iNO) has demonstrated protective effects against I/R injury in various organ systems.
Purpose of the Study:
- To investigate the neuroprotective potential of inhaled nitric oxide (iNO) in a mouse model of transient focal cerebral ischemia.
- To determine the optimal concentration and duration of iNO administration for reducing brain injury.
Main Methods:
- Male Swiss Webster mice underwent transient focal cerebral ischemia via middle cerebral artery occlusion (1 hour) followed by reperfusion (47 hours).
- Mice were exposed to varying concentrations (10-80 ppm) and durations (5-24 hours) of iNO immediately after occlusion.
- Infarct volume, blood flow, and inflammatory markers were assessed.
Main Results:
- Efficacy of iNO was dependent on both concentration and duration, with a U-shaped dose-response curve observed.
- Optimal neuroprotection was achieved with 8-16 hours of iNO at 20-60 ppm, showing reduced infarct volume.
- Higher concentrations (80 ppm) or prolonged durations (24 hours) diminished or abolished the beneficial effects.
- iNO was detected in the brain, and 8-hour administration improved recovery from subarachnoid hemorrhage and reduced inflammation.
Conclusions:
- Inhaled nitric oxide exhibits neuroprotective properties in focal cerebral ischemia, but its efficacy is critically dependent on precise concentration and duration.
- The findings suggest that enhanced blood flow during reperfusion may mediate iNO's protective effects.
- Further research into optimizing iNO therapy could be beneficial for treating ischemic stroke and related conditions.
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