Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
T. Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, Ronald S. Duman
Journal of Clinical Investigation April 16, 2019 DOI: 10.1172/jci126859 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | NV-5138 |
| Keywords | Mtorc1 Antidepressant Pharmacology Cell biology Signal transduction Pi3k/akt/mtor pathway |
| Citations | 88 |
| Key points | NV-5138 produced rapid and long-lasting antidepressant effects and reversed anhedonia and synaptic deficits via activation of mTORC1 signaling and BDNF release in the medial prefrontal cortex. |
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.