NSI 189 is a Benzylpiperazine-aminopyridine compound with molecular formula C₂₂H₃₀N₄O, which in studies was shown to stimulate the neurogenesis of neural cells (Allen et al., 2018) and improving mood evaluation statistics. It is a neurogenic compound that is at the experimental stage to be considered as a potential treatment for behavioral improvement during the low mood phase and neurodegenerative conditions. Trials are still underway to investigate it as an alternative for those who failed to respond to traditional medicines (Fava et al., 2016).  NSI 189 is involved in the neurogenesis of the hippocampus region of the brain which controls many important cognitive functions (Mclntyre et al., 2017).

Human Studies

Few initial studies involving human subjects were conducted but they are not conclusive as these were conducted in conditions that limited the reliability of the results (Fava et al., 2016; Papakostas et al., 2020).

In an initial phase 1B clinical trial, it has been suggested that this novel agent not only improved the evaluation of mood but also helped in the elevation of neurogenesis (Fava et al., 2016).

A phase II clinical study was conducted to check the efficacy of NSI 189 as a therapeutic agent which may help to improve mood. It is believed that this novel neurogenic compound has no links with reuptake inhibition pathways of norepinephrine or serotonin which in turn affect many things including mood. An oral dose of 40 mg administrated orally, showed positive results in improved mood evaluation. It also showed significant improvement in CogScreen measurement in multiple domains of cognition. This double-blind trial not only showed an improvement in cognitive symptoms & low mood but no intolerance or serious sided effect has been recorded which is good news for a novel compound. (Papakostas et al., 2020).

In another study, NSI 189 has been considered as a neurogenic entity and it has shown beneficial effects in cognitive function by improving neurogenesis in patients under major stress, but these studies have many limitations like smaller population size. (Mclntyre et al., 2017).

Animal Studies

There are many studies involving mouse model has been conducted in recent years which has shown good results in cognitive impairment (Liu et al., 2019).  There are many mechanisms suggested behind these results but still lacking many important aspects for it to be considered as an effective therapeutic agent. Most of the currently used pharmaceuticals for restoring mood do not show any improvement in cognitive impairment but current studies suggest that activation of hippocampal neurogenesis with NSI 189 may improve this condition (Yun et al., 2016; Anacker & Hen, 2017). Hippocampus is embedded in the temporal lobe of the brain and plays a role in memory and learning. It is believed to activate the hippocampus region thus helping not only to control the mood but activation of neurogenesis as well (Mclntyre et al., 2017).

In another study, this small molecule has shown excellent penetration to cross blood-brain barrier in mouse models thus improving neurodegenerative conditions more efficiently. Furthermore, it also showed an improvement in neurological deficits induced by a stroke in model mouses. (Acharya et al., 2016).

Besides being considered and clinically trialed to restore mood evaluation (Papakostas et al., 2020) but also studied as a neurogenesis enhancer on a rat model, which in turn could be beneficial to be used in neurodegenerative conditions. 24 weeks post-stroke results in the mouse model showed that neurons of animals show strong growth in the presence of NSI 189 suggesting a stimulation in brain recovery after neurodegenerative episode. Increased level of the neuronal marker, Microtubule-Associated Protein 2, in rats treated with NSI 189 showed a strong relationship between compound and remodeling of the brain by proliferation and neurogenesis. Authors argued repair not only happened in neuronal areas but also in non-neurogenic parts of the brain. This was supported by the evidence like upregulation of neurogenic factors like vascular endothelial growth factor (VEGF), Brain-derived neurotrophic factor (BDNF), and Glial cell-derived neurotrophic factor which are involved in the enhancement of neurogenesis. Furthermore, cell death triggered by oxygen-glucose deprivation was reversed in cultured hippocampal cells, when treated with NSI-189 (Tajiri et al., 2017).

In another study, the efficacy of NSI 189 was studied in central nervous system conditions. Central nervous system disorder may cause learning and physical disabilities and may be caused by genetic factors. For example, a missing copy of the UBE3A gene or it is malfunction can result in an altered level of Arc and Akt which results in cognitive and synaptic plasticity impairment. It has been found that administration of NSI 189 to mice, enhanced the signaling pathways to increase the transcription and translation pathways (Figure 2) thus resulting in reversal of these conditions (Liu et al., 2019). Other possible mechanisms include increasing hippocampal volume, modulating receptors like aldosterone which in turn improve resistance towards glucocorticoid, dopamine reuptake inhibitor, and TRPV1 inhibitor. All these suggested mechanisms may show an improvement in improved mood evaluation and cognitive impairment.

The central nervous system could be affected by increased levels of sugar and is a well-recognized factor for neurodegenerative diseases like cognitive impairment (Velayudhan, 2010) and neuropathy, a condition in which a nerve could be damaged in such patients. (Zochodne, 2010). In a recent study on rodent cells, it has been suggested that NSI 189 may not only stop the damage but also protect and help in the regeneration of damaged nerves (Jolivalt, 2019).

References:

Acharya, M.M., Green, K.N., Allen, B.D., Najafi, A.R., Syage, A. and Minasyan, H (2016).  Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep. ;6:31545 : DOI: 10.1038/srep31545

Allen, B. D., Acharya, M. M., Lu, C., Giedzinski, E., Chmielewski, N. N., Quach, D., Hefferan, M., Johe, K. K., & Limoli, C. L. (2018). Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189. Radiation research, 189(4), 345–353. DOI: 10.1667/RR14879.1

Anacker. C. and Hen, R. (2017) Adult hippocampal neurogenesis and cognitive flexibility-linking memory and mood. Nat Rev Neurosci. ;18:335–46:  DOI: 10.1038/nrn.2017.45

Fava, M., Johe, K., Ereshefsky, L., Gertsik, L.G., Englishm, B.A., Bilello, J.A., Thurmond, L.M., Johnstone, J., Dickerson, B,C,, Makris, N,, Hoeppner, B.B., Flynn, M., Mischoulon, D., Kinrys, G, and Freemanm M,P (2016) A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients. Mol Psychiatry, 21(10):1372-80. DOI: https://doi.org/10.1038/mp.2015.178

Jolivalt, C.G., Marquez, A., Quach, D., Navarro., Diaz, M.C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D.R., Fernyhough, P., Johe, K. and Calcutt, N.A (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes, 68(11):2143-2154. : DOI: 10.2337/db19-0271.

Liu, Y., Johe, K., Sun, J., Hao, X., Wang, Y.,  Bi, X., &  Baudry, M. (2019), 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, Neuropharmacology, 144, 337-344. DOI: 10.1016/j.neuropharm.2018.10.038.

McIntyre, R.S., Johe, K., Rong, C. & Lee, Y.  (2017) The neurogenic compound, NSI-189 phosphate: a novel multi-domain treatment capable of pro-cognitive and antidepressant effects, Expert Opinion on Investigational Drugs, 26:6, 767-770.: DOI: 10.1080/13543784.2017.1324847

Papakostas, G. I., Johe, K., Hand, H., Drouillard, A., Russo, P., Kay, G., Kashambwa, R., Hoeppner, B., Flynn, M., Yeung, A., Martinson, M. A., & Fava, M. (2020). A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder. Molecular psychiatry, 25(7), 1569–1579. DOI: 10.1038/s41380-018-0334-8

Tajiri, N., Quach, D.M., Kaneko, Y., Wu, S., Lee, D., Lam, T., Hayama, K.L., Hazel, T.G., Johe, K., Wu, M. C & Borlongan, C.V (2017). NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats, Journal of cellular physiology, 232, 2731-2740. DOI: https://doi.org/10.1002/jcp.25847

 Velayudhan L, Poppe M, Archer N, Proitsi P, Brown RG, Lovestone S. (2010) Risk of developing dementia in people with diabetes and mild cognitive impairment. Br J Psychiatry ;196:36–40: DOI: 10.1192/bjp.bp.109.067942

Yun, S,, Reynolds, R.P., Masiulis, I. and  Eisch, A.J.  (2016) Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis. Nat Med. 22:1239–47: DOI: 10.1038/nm.4218

Zochodne, D.W. (2010) Sensory neurodegeneration in diabetes: beyond glucotoxicity. Int Rev Neurobiol, 127:151–180: DOI: 10.1016/bs.irn.2016.03.007