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

J Cell Physiol. 2017 Oct;232(10):2731-2740. doi: 10.1002/jcp.25847. Epub 2017 Apr 25.


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.

Keywords: behavioral recovery; cerebral ischemia; neurite outgrowth; neurogenesis; pharmacotherapy; trophic factors.

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Brain / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / psychology
  • Ki-67 Antigen / metabolism
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Motor Activity / drug effects*
  • Neurogenesis / drug effects*
  • Neuronal Outgrowth / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Piperazines / pharmacology*
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Time Factors


  • Aminopyridines
  • Brain-Derived Neurotrophic Factor
  • Ki-67 Antigen
  • MAP2 protein, rat
  • Microtubule-Associated Proteins
  • NSI-189
  • Neuroprotective Agents
  • Piperazines

Associated data

  • ClinicalTrials.gov/NCT02695472