Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation
Autor: | Catharine H. Duman, George P. Vlasuk, Taro Kato, Santosh Pothula, Rong-Jian Liu, Eddine Saiah, Seung Hahm, Ronald S. Duman, Rosemarie Terwilliger |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine Stimulation mTORC1 Mechanistic Target of Rapamycin Complex 1 Blood–brain barrier Synaptic Transmission Rats Sprague-Dawley Synapse Mice 03 medical and health sciences 0302 clinical medicine medicine Premovement neuronal activity Animals Chronic stress Prefrontal cortex Heat-Shock Proteins Mice Knockout Behavior Animal Chemistry Depression Brain-Derived Neurotrophic Factor General Medicine Antidepressive Agents Rats 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Commentary Antidepressant biological phenomena cell phenomena and immunity Neuroscience Research Article Signal Transduction |
Zdroj: | J Clin Invest |
Popis: | 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. |
Databáze: | OpenAIRE |
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