NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.
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.
Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University South Florida College of Medicine, Tampa, Florida.
Naoki
N
Tajiri
Neuralstem, Inc., Rockville, Maryland.
David M
DM
Quach
Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University South Florida College of Medicine, Tampa, Florida.
Yuji
Y
Kaneko
Neuralstem, Inc., Rockville, Maryland.
Stephanie
S
Wu
Neuralstem, Inc., Rockville, Maryland.
David
D
Lee
Neuralstem, Inc., Rockville, Maryland.
Tina
T
Lam
Neuralstem, Inc., Rockville, Maryland.
Ken L
KL
Hayama
Neuralstem, Inc., Rockville, Maryland.
Thomas G
TG
Hazel
Neuralstem, Inc., Rockville, Maryland.
Karl
K
Johe
Neurodigitech, LLC., San Diego, California.
Michael C
MC
Wu
Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University South Florida College of Medicine, Tampa, Florida.
Cesar V
http://orcid.org/0000-0002-2966-9782
CV
Borlongan
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D000071446:Neuronal Outgrowth / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013997:Time Factors
D000631:Aminopyridines; D019208:Brain-Derived Neurotrophic Factor; D019394:Ki-67 Antigen; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; C000620627:NSI-189; D018696:Neuroprotective Agents; D010879:Piperazines
behavioral recovery; cerebral ischemia; neurite outgrowth; neurogenesis; pharmacotherapy; trophic factors