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

Tajiri, Naoki; Quach, David M.; Kaneko, Yuji; Wu, Stephanie; Lee, David E.; Lam, Tina I.; Hayama, Ken L.; Hazel, Thomas G.; Johe, Karl; Wu, Michael C.; Borlongan, Cesar V.

doi:10.1002/jcp.25847

Journal Cellular Physiology

2017

DOI: 10.1002/jcp.25847

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

Naoki Tajiri

¹

,

David M. Quach

²

,

Yuji Kaneko

³

et al.

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., 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… Show more

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Cited by 22 publications

(16 citation statements)

References 47 publications

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“…Our finding that NSI-189 enhanced neurite outgrowth in adult sensory neuron cultures extends the known cellular actions of this molecule to promoting regenerative growth of PNS axons. Stimulation of neurite growth is consistent with a prior report that NSI-189 increased hippocampal MAP2 expression (16), as MAP2 stabilizes microtubules and assists neurite elongation. Moreover, enhanced neurite extension by adult sensory diabetic neuron cultures was accompanied by stimulation of mitochondrial maximal respiratory capacity.…”

Section: Discussionsupporting

confidence: 92%

“…This is consistent with reports that long-term potentiation is impaired in diabetic rodents and that NSI-189 enhances long-term potentiation in mouse hippocampal slice preparations (18). Bioactivity of NSI-189 requires protein synthesis (18), and it increases expression of the neurotrophic factor BDNF by hippocampal cells in culture (16). Interestingly, BDNF is reduced in the hippocampus of db/db mice.…”

Section: Discussionsupporting

confidence: 91%

“…NSI-189 prevents impaired neurogenesis in rodent models of ischemic stroke and irradiation (16,17). The present studies demonstrate that reduced neurogenesis was prevented when NSI-189 was given to type 2 diabetic mice from the onset of diabetes at a dose of 30 mg/kg/day.…”

Section: Discussionsupporting

confidence: 49%

“…The neurogenic properties of NSI-189 were discovered using a stable line of human fetal hippocampal neural stem cells, and exploration of the properties of NSI-189 has been restricted to CNS-derived cells and brain disorders (16)(17)(18)(19)(20). Our finding that NSI-189 enhanced neurite outgrowth in adult sensory neuron cultures extends the known cellular actions of this molecule to promoting regenerative growth of PNS axons.…”

Section: Discussionmentioning

confidence: 51%

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Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

Jolivalt

¹

,

Marquez

²

,

Quach³

et al. 2019

Self Cite

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Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…Our finding that NSI-189 enhanced neurite outgrowth in adult sensory neuron cultures extends the known cellular actions of this molecule to promoting regenerative growth of PNS axons. Stimulation of neurite growth is consistent with a prior report that NSI-189 increased hippocampal MAP2 expression (16), as MAP2 stabilizes microtubules and assists neurite elongation. Moreover, enhanced neurite extension by adult sensory diabetic neuron cultures was accompanied by stimulation of mitochondrial maximal respiratory capacity.…”

Section: Discussionsupporting

confidence: 92%

“…This is consistent with reports that long-term potentiation is impaired in diabetic rodents and that NSI-189 enhances long-term potentiation in mouse hippocampal slice preparations (18). Bioactivity of NSI-189 requires protein synthesis (18), and it increases expression of the neurotrophic factor BDNF by hippocampal cells in culture (16). Interestingly, BDNF is reduced in the hippocampus of db/db mice.…”

Section: Discussionsupporting

confidence: 91%

“…NSI-189 prevents impaired neurogenesis in rodent models of ischemic stroke and irradiation (16,17). The present studies demonstrate that reduced neurogenesis was prevented when NSI-189 was given to type 2 diabetic mice from the onset of diabetes at a dose of 30 mg/kg/day.…”

Section: Discussionsupporting

confidence: 49%

“…The neurogenic properties of NSI-189 were discovered using a stable line of human fetal hippocampal neural stem cells, and exploration of the properties of NSI-189 has been restricted to CNS-derived cells and brain disorders (16)(17)(18)(19)(20). Our finding that NSI-189 enhanced neurite outgrowth in adult sensory neuron cultures extends the known cellular actions of this molecule to promoting regenerative growth of PNS axons.…”

Section: Discussionmentioning

confidence: 51%

See 2 more Smart Citations

Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

Jolivalt

¹

,

Marquez

²

,

Quach³

et al. 2019

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…We next compared in mice the efficacy of P7C3-A20 to that of NSI-189, an experimental proneurogenic drug that acts by unknown mechanisms to enhance hippocampal neurogenesis. To date, NSI-189 has shown protective efficacy in a rat model of stroke 60 , as well as a promising effect in a phase1B randomized double-blinded placebo-controlled multiple dose-escalation study in adult patients with major depressive disorder 61 . We first compared P7C3-A20 to NSI-189 for the ability to increase the net magnitude of hippocampal neurogenesis in a standard 5 day in vivo assay of BrdU-labeled cells in the dentate gyrus 17 .…”

Section: Resultsmentioning

confidence: 99%

Neuroprotective efficacy of P7C3 compounds in primate hippocampus

Bauman

¹

,

Schumann

²

,

Carlson

³

et al. 2018

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

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