ArticleThe Journal of clinical investigation2019
Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents.Frontiers in pharmacology · 2022Pooled it
- Are Resistance Training-Induced BDNF in Hemodialysis Patients Associated with Depressive Symptoms, Quality of Life, Antioxidant Capacity, and Muscle Strength? An Insight for the Muscle-Brain-Renal Axis.International journal of environmental research and public health · 2021Trial
- Targeting the SIRT6-TDO2/KYNA-mTOR axis rescues synaptic and cognitive deficits in fetal growth restriction offspring.Experimental & molecular medicine · 2026Article
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Driving proteomic imbalance in malignancy provokes proteomic catastrophe and confers tumor suppression.bioRxiv : the preprint server for biology · 2026Article
- Review
- A Time-Sensitive Plasticity Distinguishes the Rapid and Sustained Synaptic Actions of Ketamine from Its (2The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
- Exploring New Frontiers in Pharmacological Treatment of Depression: A Review on Recent Advances.Current medicinal chemistry · 2026Review
- Allosteric Conformational Locking of Sestrin2 by Leucine: An Integrated Computational Analysis of Branched-Chain Amino Acid Recognition and Specificity.Molecules (Basel, Switzerland) · 2025Article
- Cang-Ai Volatile Oil Mitigates Lipopolysaccharide-Induced Depressive-Like Behaviour in Mice by Modulating the Microglial BDNF/CREB Signaling Pathway.Molecular neurobiology · 2025Article
- Molecular Mechanisms of Depression: The Interplay Between Genes and Receptors.International journal of molecular sciences · 2025Review
- Understanding the Molecular Basis of Miller-Dieker Syndrome.International journal of molecular sciences · 2025Review
- Review
- Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges.Brain sciences · 2025Review
- Article
- Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Review
- The endogenous opioid system in the medial prefrontal cortex mediates ketamine's antidepressant-like actions.Translational psychiatry · 2024Article
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Review
- Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments.Proceedings of the National Academy of Sciences of the United States of America · 2023Review
Corrections and comments
- Commented on by
Authors and funding
9 authors.
Funding
Abstract
Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.