A role of splenic heme biosynthesis pathway in the persistent prophylactic actions of arketamine in lipopolysaccharide-treated mice.
Li Ma, Long Wang, Youge Qu, Xiayun Wan, Kenji Hashimoto
Translational Psychiatry July 25, 2023 DOI: 10.1038/s41398-023-02564-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice (and human spleen tissue from MDD patients) |
| Interventions | Arketamine Lipopolysaccharide 5-aminolaevulinic acid Succinyl acetone |
| Dose | 10 mg/kg arketamine; 1.0 mg/kg LPS; 300 mg/kg/day 5-aminolaevulinic acid; 120 mg/kg/day succinyl acetone |
| Topics | Ketamine |
| Key findings | The heme biosynthesis II pathway in the spleen mediates the prophylactic actions of arketamine against inflammation-related depression. |
Abstract
Relapse is common in remitted patients with major depressive disorder (MDD). Arketamine, an (R)-enantiomer of ketamine, has persistent prophylactic actions in an inflammatory model of depression. However, the precise mechanisms underlying these prophylactic actions remain unknown. Given the role of the brain-spleen axis in depression, we sought to identify splenic molecular targets that play a role in the prophylactic actions of arketamine. Lipopolysaccharide (LPS) (1.0 mg/kg) was administered 6 days after a single injection of arketamine (10 mg/kg) or saline. RNA-sequencing analysis found altered expression in the heme biosynthesis II pathway. Quantitative RT-PCR revealed that pretreatment with arketamine blocked increased expression of genes involved in the heme biosynthesis II pathway in LPS-treated mice, namely, 5-aminolevulinase synthase 2 (Alas2), ferrochelatase (Fech), hydroxymethylbilane synthase (Hmbs). Interestingly, there were positive correlations between the expression of these genes and spleen weight or plasma levels of pro-inflammatory cytokines. We also found higher expression of ALAS2 and FECH in the spleen from MDD patients. Pretreatment with a key intermediate precursor of heme, 5-aminolaevulinic acid (300 mg/kg/day for 3 days), caused splenomegaly, higher plasma levels of pro-inflammatory cytokines, and depression-like behavior in low-dose LPS (0.1 mg/kg)-treated mice. Interestingly, pretreatment with a heme biosynthesis inhibitor, succinyl acetone (120 mg/kg/day for 3 days), had prophylactic effects in LPS (1.0 mg/kg)-treated mice. These data suggest a novel role for the heme biosynthesis II pathway in the spleen for inflammation-related depression. Therefore, the heme biosynthesis pathway could be a new target for the prevention of relapse in MDD patients.
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 9
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. International Journal of Molecular Sciences June 20, 2024
- Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis. Neurobiology of Disease September 1, 2024
- Prophylactic effects of arketamine, but not hallucinogenic psychedelic DOI nor non-hallucinogenic psychedelic analog lisuride, in lipopolysaccharide-treated mice and mice exposed to chronic restrain stress. Pharmacology, Biochemistry, and Behavior December 1, 2023
- A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress. Pharmacology, Biochemistry, and Behavior May 1, 2024
and 4 more in the library
Cites 31
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- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine as Adjunctive Therapy in Treatment-Resistant Depression (TRD) Molecular Psychiatry October 3, 2018
and 26 more in the library