Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway.
Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni, Nicole Mariani, Carmine M. Pariante, Alessandra Borsini
The International Journal of Neuropsychopharmacology October 1, 2024 DOI: 10.1093/ijnp/pyae041 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Population | Fetal hippocampal progenitor cell line (HPC0A07/03C) |
| Interventions | sertraline venlafaxine |
| Dose | 400 nM for each ketamine enantiomer, 1 mM for sertraline and venlafaxine |
| Topics | Neuroplasticity Esketamine Ketamine |
| Keywords | Cytokines Apoptosis Hippocampal neurogenesis Kynurenine pathway Brain inflammation Ketamine therapy Cell death mechanisms |
| Citations | 12 |
| Key points | Both R- and S-ketamine prevented cytokine-induced reductions in hippocampal neurogenesis and increases in apoptosis, with protection against IL-1β-driven kynurenine pathway activation but not against IL-6-driven activation. |
Abstract
Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish. We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM). Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation. Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from 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 5
- Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review. International Journal of Molecular Sciences December 5, 2024
- Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair. Cells November 26, 2025
- Kynurenine pathway profiles as markers of ketamine response in treatment-resistant depression. Brain, Behavior, and Immunity July 5, 2026
- Targeting TLR4/PPARα-mediated neuroinflammation in the prefrontal cortex: S-ketamine and S-HNK rapidly alleviate depression-like behaviors Journal of Neuroimmunology July 1, 2026
- Age-related moderation of adjunctive psychotherapy and early life stress effects on depression symptom reductions following ketamine treatment: Initial insights from a large, naturalistic sample. Journal of Affective Disorders February 4, 2026
Cites 20
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
and 15 more in the library