Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway
Open accessAbstract
Background: 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. Methods: 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). Results: 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. Conclusions: 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.
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(R)-ketamine suppresses pro-inflammatory mediators such as IL-6 and TNF-α, which contribute to neuroinflammation.
“Additionally, (R)-ketamine’s effect on microglia has been shown to involve suppression of pro-inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which contribute to neuroinflammation [81,83].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [83]
The Results section (page unavailable) shows that R-ketamine suppressed some inflammatory cytokines in human hippocampal cells: IL-2 and IL-13 after IL-1β exposure, and IL-13 after IL-6 exposure. It does not report suppression of IL-6 or TNF-α by R-ketamine; it attributes TNF-α suppression to S-ketamine. The study does not establish the claimed effect on microglia. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe anti-inflammatory property of (R)-ketamine may enhance microglial support of neuronal health, reduce oxidative stress, and promote synaptic connectivity.
“This anti-inflammatory property of (R)-ketamine may enhance the functional role of microglia in supporting neuronal health, reducing oxidative stress, and promoting synaptic connectivity [81,83].”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [83]
The Discussion reports that (R)-ketamine attenuated cytokine increases and protected neurogenesis in human hippocampal progenitor cells, supporting its anti-inflammatory property. It does not establish enhanced microglial support, reduced oxidative stress, or increased synaptic connectivity; the Discussion says glia-related effects remain for future study. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome results are derived from secondary analyses of previously conducted studies, so the setting may not be optimal for examining BDNF variations in patients treated with ketamine.
“some of the results presented are derived from secondary analyses of previously conducted studies [80,83]; therefore, the setting may not be optimal for the objective considered (examining BDNF variations in patients treated with ketamine).”
From Variations in BDNF and Their Role in the Neurotrophic Antidepressant Mechanisms of Ketamine and Esketamine: A Review (2024) · cites this paper as [83]
The Materials and Methods section describes experiments treating hippocampal cells with ketamine, and the Discussion identifies the use of an in vitro cell line as a limitation. Searches for BDNF variation in ketamine-treated patients and for secondary analyses found no passage addressing the claimed limitation. The paper therefore cannot verify this attribution. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Self-citation
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Kynurenine pathway profiles as markers of ketamine response in treatment-resistant depression
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- Authors
- Mandal, G., Kirkpatrick, M., Alboni, S., Mariani, N., Pariante, C. M., & Borsini, A.
- Affiliations
- King's College London (GB)
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- Borsini, Alessandra
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2024-09-19
- Volume
- 27
- Issue
- 10
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC11450635
- OpenAlex
- W4402715472
- Cited by
- 15
- References
- 77
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 2
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, other-oa)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- UK Medical Research Council (MR/L014815/1, MR/J002739/1, MR/N029488/1)
- European Commission Horizon 2020 (SC1-BHC-01-2019)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- ketamine, esketamine, kynurenine pathway, hippocampal neurogenesis, neuroinflammation, IL-1β, interleukin-6, indoleamine 2,3-dioxygenase, apoptosis, depression, antidepressant mechanism, cytokines, sertraline
- MeSH terms
- Venlafaxine Hydrochloride, Antidepressive Agents, Cell Line, Hippocampus, Humans, Inflammation, Ketamine, Kynurenine, Stereoisomerism, Interleukin-6, Apoptosis, Sertraline, Interleukin-1beta, Neurogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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