Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors.
Rosa Estrada-Reyes, Daniel B Quero-Chávez, Salvador Alarcón-Elizalde, Montserrat G Cercós, Citlali Trueta, Luis A Constantino-Jonapa, Julián Oikawa-Sala, Jesús Argueta, Ricardo Cruz-Garduño, Margarita L Dubocovich, Gloria Benítez-King
Molecules September 1, 2022 DOI: 10.3390/molecules27175650 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical in vitro study Peer reviewed |
|---|---|
| Population | Cloned human olfactory neuronal precursor cells |
| Interventions | Ketamine Melatonin |
| Measures | cell clusters > 50 µm in diameter positively stained for nestin, doublecortin, BrdU and Ki67 |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Antidepressants Melatonin Olfactory neuronal precursors |
| Key points | The ketamine/melatonin combination increased neurogenesis in human olfactory neuronal precursor cells, measured as formation of cell clusters over 50 micrometers positive for nestin, doublecortin, BrdU, and Ki67, at doses of each drug that were ineffective alone. The authors report the effect is mediated by melatonin receptors, CaM Kinase II, and CaM antagonism, and propose this could have clinical advantages for fast treatment of depression. |
Abstract
Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 2
Cites 3
- Psychedelic Effects of Ketamine in Healthy Volunteers Anesthesiology 1998
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Low Doses of Ketamine and Melatonin in Combination Produce Additive Antidepressant-like Effects in Mice International Journal of Molecular Sciences August 26, 2021