Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Taro Kato, … , Seung Hahm, Ronald S. Duman
Taro Kato, … , Seung Hahm, Ronald S. Duman
Published April 16, 2019
Citation Information: J Clin Invest. 2019;129(6):2542-2554. https://doi.org/10.1172/JCI126859.
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Research Article Neuroscience

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

Abstract

Preclinical studies demonstrate that rapid-acting antidepressants, including ketamine, require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity and endocrine and metabolic signals, notably including 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 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 brain-derived neurotrophic factor (BDNF) release, as the behavioral responses were blocked by infusion of a BDNF-neutralizing Ab into the medial prefrontal cortex (mPFC) or, in mice, with a knockin of a BDNF polymorphism that blocked 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 produces rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin may be an attractive approach for the development of rapid-acting antidepressants.

Authors

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

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Figure 2

Single-dose NV-5183 produces long-lasting antidepressant effects, and repeated low-dose NV-5138 also produces antidepressant effects.

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Single-dose NV-5183 produces long-lasting antidepressant effects, and re...
(A) Three or seven days after NV-5138 (160 mg/kg) or ketamine (10 mg/kg) administration, the FST was conducted. Three days after the FST, the NSFT was conducted. Both NV-5138 and ketamine significantly decreased immobility time in the FST 3 and 7 days after administration (B and D) (NV-5138; F2,21 = 5.82, P < 0.01, ketamine; F2,21 = 5.47, P < 0.05) but had no effect on latency to feed in the NSFT on day 10 (C and E). (F) Low-dose NV-5138 was administered once a day for 7 days, and ketamine was administered on alternate days over the same time frame. Twenty-four hours after the last administration, behavioral studies were conducted over the next 3 days (G–J). Both ketamine and 80 mg/kg of NV-5138 significantly decreased immobility time in the FST (I) (F3,28 = 4.05, P < 0.05) and latency to feed in the NSFT (K) (F3,28 = 7.29, P < 0.001). No significant effects were seen in (H) locomotor activity (F3,27 = 0.500, P > 0.05) or (J) HCF (F3,28 = 0.380, P > 0.05). The results are shown as mean ± SEM. n = 8/group. *P < 0.05; **P < 0.01, Tukey’s multiple comparison test, following significant results of 1-way ANOVA (B, D, G–J) or Student’s t test (C and E).