Abstract
Introduction: RNS60 is an experimental treatment containing oxygen nanobubbles. RNS60 has previously been shown to reduce neuroinflammation and increase neuronal survival in animal models of multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson’s diseases, and traumatic brain injury. RNS60 is in phase 2 clinical testing as a treatment for ALS and acute ischemic stroke. Since RNS60 is protective in a variety of pathophysiological conditions that activate neurodegeneration, we evaluated whether RNS60 can reduce brain injury and rescue cognitive functions in a mouse model of ischemic stroke. Methods: Male C57BL/6J mice (4 months old) were subjected to transient (60 min) occlusion of the middle cerebral artery (tMCAo) followed by reperfusion, or sham surgery. We investigated the effects of post-stroke RNS60 treatment for 3 or 13 days (beginning 1 hour after reperfusion, 0.2 mL administered i.p., 1/day). Two control treatments (normal saline or oxygenated saline without nanobubbles) were used for comparison. Experimenters were blinded to the treatment groups throughout the study. To assess the post-stroke effects of RNS60 treatments, we performed multiple neurobehavioral tests that included modified neurological severity score (mNSS), novel object recognition (NOR), active place avoidance (APA), and the conflict variant of APA. Brains were collected for assessment of infarct volumes or for immunofluorescence measurements of amyloid, neurons, microglia, and axons. Results: Three days of treatment with RNS60 reduced brain infarction, edema, sensory-motor, and cognitive deficits. Thirteen days of treatment reduced brain infarction, amyloid pathology, neuronal cell death, microglial activation, and white matter damage. Noteworthy behavioral effects included recovery of memory during NOR and cognitive flexibility in the APA conflict variant. Conclusion: RNS60 treated mice exhibit significant acute and chronic protection of brain cells and neurobehavior after experimental stroke. Our data support the evaluation of RNS60 in clinical stroke trials.
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