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 4

Antidepressant actions of NV-5138 are dependent on activation of mTORC1 signaling.

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Antidepressant actions of NV-5138 are dependent on activation of mTORC1 ...
(A) Rats were administered vehicle or NV-5138 (160 mg/kg) and PFC dissections were collected 1 hour later. (B) Diagram showing postsynaptic signaling. Levels of the phosphorylated and activated forms of (C) mTOR, (D) p70S6K, and (E) 4EBP1 as determined by Western blot analysis were increased by NV-5138 and ketamine; levels of total proteins or GAPDH were also measured to control for loading differences. Results are shown as mean ± SEM. n = 6/group. *P < 0.05; **P < 0.01, Student’s t test. (F) Rats were implanted with bilateral cannula in the mPFC and allowed to recover for approximately 2 weeks. (G) The mTORC1 inhibitor rapamycin was infused into the mPFC 30 minutes prior to administration of vehicle or NV-5138. Twenty-four hours after NV-5138 administration, behavioral studies were initiated and conducted over the next 3 days (H–K). NV-5138 treatment significantly decreased immobility time and latency to feed, but these effects were blocked by rapamycin in (H) the FST (F2,17 = 20.46, P < 0.001) and (J) the NSFT (F2,17 = 5.36, P < 0.05), respectively. No significant effects were seen in (I) LMA (F2,17 = 0.200, P > 0.05) or (K) HCF (F2,17 = 0.814, P > 0.05). Results are shown as mean ± SEM. n = 6–7. *P < 0.05; **P < 0.01, Tukey’s multiple comparisons test, following significant results of 1-way ANOVA. Rap, rapamycin.