Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK)
| Autor: | Milena Rossmanith, Jan Engelmann, Nils C. Gassen, Marianne B. Müller, Natarajan Perumal, Michael A. van der Kooij, Giulia Treccani, Annika Hasch, Caroline Manicam, David P. Herzog, Klaus Lieb, Tanja Jene, Jens Nadig, Franz H. Grus |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
Neurophysiology and neuropsychology animal structures Hydroxynorketamine Physiology Glucocorticoid receptor signaling Antidepressant CSF Neurosciences. Biological psychiatry. Neuropsychiatry Biology Pharmacology Biochemistry Cellular and Molecular Neuroscience Endocrinology Glucocorticoid receptor Neurotrophic factors medicine Original Research Article Ketamine (2R 6R)-Hydroxynorketamine RC346-429 Molecular Biology PI3K/AKT/mTOR pathway Endocrine and Autonomic Systems QP351-495 Mechanism of action embryonic structures Neurology. Diseases of the nervous system medicine.symptom Signal transduction RC321-571 |
| Zdroj: | Neurobiology of Stress, Vol 15, Iss, Pp 100404-(2021) Neurobiology of Stress, 15:100404 Neurobiology of Stress Herzog, D P, Perumal, N, Manicam, C, Treccani, G, Nadig, J, Rossmanith, M, Engelmann, J, Jene, T, Hasch, A, van der Kooij, M A, Lieb, K, Gassen, N C, Grus, F H & Müller, M B 2021, ' Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK) ', Neurobiology of Stress, vol. 15, 100404 . https://doi.org/10.1016/j.ynstr.2021.100404 |
| ISSN: | 2352-2895 |
| DOI: | 10.1016/j.ynstr.2021.100404 |
| Popis: | Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK's rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|