Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

Kato, Taro; Pothula, Santosh; Liu, Rong-Jian; Duman, Catharine H.; Terwilliger, Rosemarie; Vlasuk, George P.; Saiah, Eddine; Hahm, Seung; Duman, Ronald S.

doi:10.1172/jci126859

Cited by 63 publications

(61 citation statements)

References 50 publications

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“…Clinical targeting of the mTOR pathway to rescue RGC degeneration may involve pharmacological activation of the pathway. Recently, a small molecule, NV-5138, has been shown to activate mTORC1 both in vivo and in vitro (Kato et al, 2019;Sengupta et al, 2019). Alternatively, to address the concern that pharmacological activation of the mTOR pathway may affect the function of other cell types because of its ubiquitous presence, RGCs could be targeted for silencing the TSC2 gene by adeno-associated virus sera 2 (AAV2) transduction, which is RGC specific in the adult retina (Hanlon et al, 2017;Harvey et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

et al. 2019

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The poor axon regeneration in the central nervous system (CNS) often leads to permanent functional deficit following disease or injury. For example, degeneration of retinal ganglion cell (RGC) axons in glaucoma leads to irreversible loss of vision. Here, we have tested the hypothesis that the mTOR pathway regulates the development of human RGCs and that its recruitment after injury facilitates axon regeneration. We observed that the mTOR pathway is active during RGC differentiation, and using the induced pluripotent stem cell model of neurogenesis show that it facilitates the differentiation, function and neuritogenesis of human RGCs. Using a microfluidic model, we demonstrate that recruitment of the mTOR pathway facilitates human RGC axon regeneration after axotomy, providing evidence that the recapitulation of developmental mechanism(s) might be a viable approach for facilitating axon regeneration in the diseased or injured human CNS, thus helping to reduce and/or recover loss of function.

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Section: Discussionmentioning

confidence: 99%

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

et al. 2019

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“…Lysine-specific demethylase 1 (LSD1) suppresses oxidized low-density lipoprotein (Ox-LDL)-induced inflammation by promoting Sestrin2-mediated PI3K/AKT/mTOR pathway activation (Zhuo et al, 2019). Recently, Navitor Pharmaceuticals developed Sestrin2-specific inhibitor, a leucine analog NV-5138, and try to treat the major depressive disorder (MDD) by activating mTORC1 in the brain (Hasegawa et al, 2019;Kato et al, 2019;Sengupta et al, 2019). However, one of the main causes of obesity, inflammation and metabolic disease is the hyperactivation of mTORC1, so the development of Sestrin2-specific activator compound or drug would be a potential therapeutic (Dong, 2015).…”

Section: Introduction Of Sestrinsmentioning

confidence: 99%

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Fay

Cyuzuzo

et al. 2020

Front. Cell Dev. Biol.

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Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.

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“…In vivo analysis of extracellular serotonin after administration of Alk-S-Cit. SSRIs increase the serotonin level in the synaptic cleft by binding to SERT, especially in the medial prefrontal cortex, a brain region implicated in antidepressant effects (24). The medial prefrontal cortex receives inputs from the dorsal raphe nucleus, the largest serotonergic nucleus in the murine brain, and exhibits increased levels of extracellular serotonin after the administration of SSRIs (25).…”

Section: Resultsmentioning

confidence: 99%

Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain

Tanuma¹,

Kasai²,

Bando³

et al. 2020

JCI Insight

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Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation

Cited by 63 publications

References 50 publications

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain

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