Neuroscience Research Compound · For laboratory research use only
Also known as NSI-189 Phosphate
NSI-189 ((4-benzylpiperazin-1-yl)-[2-(3-methylbutylamino)pyridin-3-yl]methanone) is a benzylpiperazine-aminopyridine small molecule, usually studied as its phosphate salt. It was developed on the basis of preclinical data showing stimulation of neurogenesis in human hippocampus-derived neural stem cells in vitro and in mouse hippocampus in vivo3.
Preclinical research has examined it in rat models of ischaemic stroke, cranial irradiation and type 2 diabetes, and in mouse models of Angelman syndrome and of type 1 and type 2 diabetes1,2,3,4,5. Two clinical trials in major depressive disorder have been published6,7; the phase 1B report carries a published erratum.
As described in the research literature
As described in the research literature, the mechanism behind the neurogenic activity of NSI-189 has not been fully defined. In acute hippocampal slices, NSI-189 increased the magnitude of theta burst-induced long-term potentiation in slices from wild-type and Angelman syndrome model mice, and its effects were associated with activation of the TrkB and Akt pathways3.
In hippocampal cells exposed to oxygen glucose deprivation and reperfusion, NSI-189 treatment was associated with reduced cell death, increased Ki67 and MAP2 expression and upregulation of BDNF and stem cell factor1. In cultured adult rat sensory neurons it enhanced neurite outgrowth and mitochondrial function4, and in Zucker diabetic fatty rats it was associated with changes in respiratory complex subunit expression and activity in brain cortex and with AMPK activity in dorsal root ganglia5.
What published studies have examined
Sprague-Dawley rats with middle cerebral artery occlusion were followed for motor and neurological measures for up to 24 weeks, with histological assessment of MAP2 immunoreactivity in hippocampus and cortex and parallel in vitro oxygen glucose deprivation studies1.
Sources [1]
Long-Evans rats given a fractionated cranial irradiation protocol were assessed on five behavioural tasks, followed by analysis of neurogenesis, hippocampal volume and activated microglia2.
Sources [2]
Hippocampal slices from wild-type and Angelman syndrome model mice were used to study long-term potentiation, and cognitive and motor tasks were assessed in the model mice, with TrkB and Akt pathway analysis3.
Sources [3]
Mouse models of type 1 and type 2 diabetes were used to examine small and large fibre peripheral neuropathy, hippocampal neurogenesis, synaptic markers and volume, and memory4. In Zucker diabetic fatty rats, nerve conduction, tactile and thermal sensitivity, cognitive measures and mitochondrial function in dorsal root ganglia and cortex were assessed5.
A phase 1B randomised, double-blind, placebo-controlled study in patients with major depressive disorder assessed safety, pharmacokinetics and exploratory efficacy measures6. A phase 2 double-blind, placebo-controlled trial in outpatients with major depressive disorder used a sequential parallel comparison design, with the Montgomery-Asberg Depression Rating Scale as the primary outcome measure7.
NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.
Tajiri N, Quach DM, Kaneko Y, et al. Journal of Cellular Physiology, 2017.
Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189.
Allen BD, Acharya MM, Lu C, et al. Radiation Research, 2018.
Enhancement of synaptic plasticity and reversal of impairments in motor and cognitive functions in a mouse model of Angelman Syndrome by a small neurogenic molecule, NSI-189.
Liu Y, Johe K, Sun J, et al. Neuropharmacology, 2019.
Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189.
Jolivalt CG, Marquez A, Quach D, et al. Diabetes, 2019.
Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes.
Jolivalt CG, Aghanoori MR, Navarro-Diaz MC, et al. Journal of Diabetes Research, 2022.
A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.
Fava M, Johe K, Ereshefsky L, et al. Molecular Psychiatry, 2016.
A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder.
Papakostas GI, Johe K, Hand H, et al. Molecular Psychiatry, 2020.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.