The resilient phenotype elicited by ketamine against inflammatory stressors-induced depressive-like behavior is associated with NLRP3-driven signaling pathway.
A. Camargo, A. P. Dalmagro, Ingrid A V Wolin, Manuella P. Kaster, A. Rodrigues
Journal of Psychiatric Research September 30, 2021 DOI: 10.1016/j.jpsychires.2021.09.057 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Dose | 5 mg/kg, 1 mg/kg |
| Duration | Single administration 1 week before stressor; behavioral tests and tissue collection after stressor |
| Topics | Esketamine Ketamine |
| Post-publication review | 1 comment on PubPeer (opens in new tab) · last active October 2021 |
| Key findings | Prophylactic ketamine (5 mg/kg) prevented depressive-like behavior induced by LPS or TNF-α in mice, an effect associated with suppression of NLRP3 inflammasome signaling in the ventral hippocampus. |
Abstract
Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS - 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-α - 0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-α administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-α, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1β in this brain region, while TNF-α only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-α administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 8
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
- Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile Drug Discovery Today February 1, 2023
- Ketamine and serotonergic psychedelics: An update on the mechanisms and biosignatures underlying rapid-acting antidepressant treatment Neuropharmacology January 13, 2023
- Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior. Molecular Psychiatry June 1, 2025
- Prophylactic Ketamine: Current Knowledge and Future Directions. Biological Psychiatry March 28, 2025
and 3 more in the library
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and 4 more in the library