NV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signaling

Abstract

Growing evidence implicates altered mTORC1 signaling cascades in the pathophysiology of depression, suggesting that direct modulation of mTORC1 signaling may offer novel therapeutic potential. In this issue of the JCI, Kato and colleagues reported that administration of NV-5138, a recently developed synthetic leucine analog, has a rapid and sustained antidepressant action in rat models via activation of mTORC1 signaling. The investigators also found that the antidepressant effect of NV-5138 is mediated by upregulation of brain-derived neurotrophic factor (BDNF) signaling and that NV-5138 treatment produces rapid synaptic responses in the medial prefrontal cortex. These findings highlight the direct activation of mTORC1 signaling as a potential pharmacological intervention for the treatment of depression.

Figure 1. Antidepressant action of NV-5138 via direct activation of mTORC1 signaling.

Rapamycin-sensitive mTORC1 signaling regulates the production of synaptic proteins and BDNF via p70S6K and 4E-BP1 signaling pathways. NV-5138, a synthetic leucine analog, binds sestrins and releases sestrins from GATOR2, resulting in mTORC1 activation and producing fast antidepressant effects. Note that mTORC1 signaling also regulates inflammatory machinery via NF-κB and STAT3 signaling pathways, suggesting that aberrant inflammatory mechanisms underlying depressive symptoms may also be targetable via modulation of mTORC1 signaling.