Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 232, Issue 10, Pages 2731-2740Publisher
WILEY
DOI: 10.1002/jcp.25847
Keywords
behavioral recovery; cerebral ischemia; neurite outgrowth; neurogenesis; pharmacotherapy; trophic factors
Categories
Funding
- National Institutes of Health, National Institute of Neurological Disorders and Stroke [1R01NS071956, 1R01NS090962, 1R21NS089851]
- Department of Defense [W81XWH-11-1-0634]
- James and Esther King Foundation for Biomedical Research Program
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Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI-189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti-depressant drug in a clinical trial (Fava et al., 2015, Molecular Psychiatry, DOI: 10.1038/mp. 2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials. gov, 2016, ClinicalTrials. gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI-189 in adult Sprague-Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke-induced motor and neurological deficits, which was maintained up to 24 weeks post-stroke. Histopathological assessment of stroke brains from NSI-189-treated animals revealed significant increments in neurite outgrowth as evidencedbyMAP2immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI-189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI-189 treatment characterized by significant attenuation of OGD/R-mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI-189 as a therapeutic agent well beyond the initial 6-hr time window to accelerate and enhance the overall functional improvement in the initial6months post stroke.
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