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NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

ABSTRACT: 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., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , 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 evidenced by MAP2 immunoreactivity 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 initial 6 months post stroke.

SUBMITTER: Tajiri N

PROVIDER: S-EPMC5518191 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

Tajiri Naoki N Quach David M DM Kaneko Yuji Y Wu Stephanie S Lee David D Lam Tina T Hayama Ken L KL Hazel Thomas G TG Johe Karl K Wu Michael C MC Borlongan Cesar V CV

Journal of cellular physiology 20170425 10

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., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depressio ...[more]

PMID: 28181668

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NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

Publications

NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

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