Development of novel activators of mTOR signaling pathway as adjunct therapy in treatment-resistant depression (NW24-04-00422)
Basic information
Investigator: doc. RNDr. Zdeňka Bendová, Ph.D.
Main recipient: National Institute of Mental Health (NIMH)
Co-recipient: University of Pardubice, University of Hradec Kralove
Research period: 1/5/2024 – 31/12/2027
Total budget: 13,496,000 CZK
NIMH budget: 4,623,000 CZK
Supported by: Czech Health Research Council (AZV ČR)
Annotation
Depression is a mental illness, with typical symptoms including low mood and aversion to activity. Additionally, numerous studies point to a significant correlation between depression and circadian rhythm disorders. Depression that does not achieve a clinically relevant effect after two treatment courses is considered treatment-resistant depression (TRD). The mTOR (mechanistic target of rapamycin) signaling pathway is involved in a broad range of brain functions, including neurogenesis, neuron survival, synapse formation, and synaptic plasticity. Moreover, a bidirectional relationship between circadian clocks and mTOR has been discovered. Dysregulation of the mTOR signaling pathway has been demonstrated in various human diseases, including depression. Recent post-mortem studies have highlighted significant deficits in mTOR signaling in the prefrontal cortex of individuals diagnosed with depressive disorder. More detailed animal studies have revealed that the rapid antidepressant response to NMDA receptor antagonists, such as ketamine, is mediated by the rapid activation of the mTOR signaling pathway, leading to increased concentrations of synaptic signaling proteins and an enhanced number and function of new synapses in the rat prefrontal cortex. Based on the above findings, the co-administration of ketamine and mTOR signaling pathway activators could represent a completely new approach to combating treatment-resistant depression. Probably the most studied mTOR activator is MHY1485. The aim of the present project is to find new mTOR activators derived from MHY1485, which could be used as adjunctive treatment for depression, including TRD. A multidisciplinary approach will be used, involving the identification, synthesis, and in vitro and primarily in vivo evaluation of new mTOR activators to demonstrate whether activation of the mTOR signaling pathway is a suitable target for further research in the area of TRD.