Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, Ronald S. Duman
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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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 5

BDNF is required for antidepressant actions of NV-5138.

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BDNF is required for antidepressant actions of NV-5138. (A–E) The antide...
(A–E) The antidepressant actions of NV-5138 are blocked by infusion of BDNF nAb into the mPFC. (A) BDNF nAb or control IgG (0.5 μg/side) was infused into the mPFC 30 minutes prior to administration of vehicle or NV-5138 (160 mg/kg, p.o.). (B and D) NV-5138 significantly decreased immobility time (B) in the FST (effect of NV-5138: F1,29 = 14.6, P < 0.001; mPFC infusion: F1,29 = 13.4, P < 0.001; interaction: F1,29 = 14.9, P < 0.001) and latency to feed (D) in the NSFT (effect of NV-5138: F1,29 = 39.4, P < 0.001; mPFC infusion: F1,29 = 11.2, P = 0.002; interaction: F1,29 = 18.0, P < 0.001), and these effects were blocked by infusion of the BDNF nAb. (C and E) There were no significant effects on locomotor activity (effect of NV-5138: F1,30 = 0.01, P = 0.92; mPFC infusion: F1,30 = 0.07, P = 0.79; interaction: F1,30 = 0.03, P = 0.86) or HCF (effect of NV-5138: F1,30 = 0.11, P = 0.74; mPFC infusion: F1,30 = 2.93, P = 0.1; interaction: F1,30 = 1.23, P = 0.28). (F–J) The antidepressant actions of NV-5138 are attenuated in BDNF Val66Met knockin mice. (F) Experimental time line for behavioral testing of animals after vehicle or NV-5138 administration. In the BDNF Val/Val mice, NV-5138 treatment significantly decreased immobility time (G) in the FST (effect of NV-5138: F1,64 = 12.7, P < 0.001; genotype: F2,64 = 1.88, P = 0.16; interaction: F2,64 = 3.98, P = 0.02) and latency to feed (I) in the NSFT (effect of NV-5138: F1,65 = 13, P < 0.001; genotype: F2,65 = 12.8, P < 0.001; interaction: F2,65 = 3.4, P = 0.04) that were blocked in Val/Met and Met/Met mice. No significant effects were observed in (H) LMA (effect of NV-5138: F1,64 = 3.39, P > 0.05; genotype: F2,64 = 0.59, P = 0.56; interaction: F2,64 = 0.06, P = 0.94) or (J) HCF (effect of NV-5138: F1,65 = 0.065, P = 0.80; genotype: F2,65 = 0.52, P = 0.60; interaction: F2,65 = 0.58, P = 0.56). Results are shown as mean ± SEM. n = 7–9/group (A–E); n = 5–16/group (F–J). *P < 0.05; **P < 0.01; ***P < 0.001 (A–J), 2-way ANOVA and Tukey’s post hoc test.