Impaired cognitive performance in endothelial nitric oxide synthase knock-out mice after ischemic stroke, a pilot study

ABSTRACTObjectivesCognitive dysfunction and dementia are common following ischemic stroke. Endothelial nitric oxide synthase (eNOS) has been found to play an important role in neurological function and cognition. The purpose of the present study was to assess the specific role of eNOS in cognitive performance after stroke.DesignMale wildtype (WT) and mice lacking eNOS (eNOS-/-) underwent middle cerebral artery occlusion (MCAO) or sham-surgery. Primary outcomes were repeated measures of neurological score, limb asymmetry, sensory/motor function and spatial memory/learning assessed at intervals up to 28-days post-surgery. Group differences in brain microglia activation and infiltration, and levels of interferon-gamma (IFN-γ) were examined.ResultsThere was no genotype x surgery interaction effect on the pattern of change in neurological score, limb asymmetry, or sensory motor function across the 28-days post-surgery. In the Morris Water Maze, eNOS-/- MCAO mice displayed learning and memory deficits not evident in WT MCAO mice. Poorer spatial memory and learning in eNOS-/- MCAO mice was associated with a reduction in the number of activated microglia in the striatum on the lesion side and decreased brain tissue levels of IFN-γ.ConclusionsOur data support a role for eNOS in cognitive performance after stroke. This finding may lead to the development of novel interventions to treat post-stroke cognitive deficits. Objectives Cognitive dysfunction and dementia are common following ischemic stroke. Endothelial nitric oxide synthase (eNOS) has been found to play an important role in neurological function and cognition. The purpose of the present study was to assess the specific role of eNOS in cognitive performance after stroke. Design Male wildtype (WT) and mice lacking eNOS (eNOS-/-) underwent middle cerebral artery occlusion (MCAO) or sham-surgery. Primary outcomes were repeated measures of neurological score, limb asymmetry, sensory/motor function and spatial memory/learning assessed at intervals up to 28-days post-surgery. Group differences in brain microglia activation and infiltration, and levels of interferon-gamma (IFN-γ) were examined. Results There was no genotype x surgery interaction effect on the pattern of change in neurological score, limb asymmetry, or sensory motor function across the 28-days post-surgery. In the Morris Water Maze, eNOS-/- MCAO mice displayed learning and memory deficits not evident in WT MCAO mice. Poorer spatial memory and learning in eNOS-/- MCAO mice was associated with a reduction in the number of activated microglia in the striatum on the lesion side and decreased brain tissue levels of IFN-γ. Conclusions Our data support a role for eNOS in cognitive performance after stroke. This finding may lead to the development of novel interventions to treat post-stroke cognitive deficits. S Li and Y Wang contributed equally. The study was performed at Stroke Biological Recovery Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, the teaching affiliate of Harvard Medical School, Charlestown, MA 02129 Co-coresponding author and eighth author: Lisa J. Wood, PhD, RN, FAAN, School of Nursing, Fatigue Research Laboratory, MGH Institute of Health Professions, 96 13th street, Charlestown, MA 02129, USA Phone: 617-724-3454, Email: ljwood@mghihp.edu Corresponding author and Last author: Qing Mei Wang, MD, PhD, Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The teaching affiliate of Harvard Medical School, 96 13th street, Charlestown, MA 02129, USA. Email: wang.qingmei@mgh.harvard.edu Disclosures: This work was funded by the National Institutes of Health [grant number HD074668, 2013-2016). The funding organization was not involved in study design, in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. An abstract was presented at the annual meeting of American Association of Physiatrists in February 2016. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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