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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

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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 3

NV-5138 reverses the behavioral and synaptic deficits caused by CUS.

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NV-5138 reverses the behavioral and synaptic deficits caused by CUS.
(A)...
(A) Schematic for CUS experiment and effect of NV-5138 (160 mg/kg, day 20 of CUS) on the SPT and NSFT (on days 21 and 22 of CUS). CUS was continued throughout the behavioral testing and tissue sampling on day 26. After a short washout period, a second dose of NV-5138 was administered on CUS day 25 and tissue was collected on day 26. (B–D) Results are the mean ± SEM. n = 13–14/group. (B) CUS decreased sucrose preference and NV-5138 reversed this effect; there was a significant interaction between CUS and NV-5138 administration (F1,50 = 5.20, P < 0.05, effect of CUS: F1,50 = 2.21, P > 0.05, effect of NV-5138: F1,50 = 3.27, P > 0.05). Also, a 3-way ANOVA analysis revealed a significant interaction among CUS, NV-5138 administration, and sucrose consumption (F1,50 = 4.02, P = 0.05). (C) CUS increased the latency to feed in NSFT, and NV-5138 reversed this effect (F1,50 = 1.89, P > 0.05, effect of CUS: F1,50 = 17.52, P < 0.001, effect of NV-5138: F1,50 = 43.4, P < 0.0001). (D) There was no significant effect on HCF (F1,50 = 0.0679, P > 0.05. (E) CUS significantly decreased body weight (F1,104 = 47.06, P < 0.0001, effect of day: F1,104 = 2612, P < 0.0001, effect of CUS: F1,50 = 49.86, P < 0.0001). Results are shown as mean ± SEM. n = 13–14/group. *P < 0.05; **P < 0.01, 2-way ANOVA and Tukey’s multiple comparison test. (F and G) CUS decreased levels of the postsynaptic proteins GluR1 and PSD95 in PFC, and NV-5138 reversed these deficits (GluR1, F2,19 = 7.95, P < 0.01; PSD95, F2,19 = 6.31, P < 0.01). Results are shown as mean ± SEM. n = 7–8/group. *P < 0.05; **P < 0.01, ****P < 0.001, 1-way ANOVA (B–D, F, G) and Student’s t test (E). NS, NSFT; V, vehicle.
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