Translational Psychiatry
December 15, 2017
Chun Yang, Youge Qu, Yuko Fujita et al.
231 citations
The gut microbiota-brain axis is implicated in depression, and (R)-ketamine shows more potent and longer-lasting antidepressant effects than (S)-ketamine. In a chronic social defeat stress mouse model of depression, fecal 16S ribosomal RNA gene sequencing revealed that both enantiomers attenuated increases in Deltaproteobacteria levels. (R)-ketamine, but not (S)-ketamine, also reversed reductions in Mollicutes levels. At the genus level, both enantiomers attenuated decreases in Butyricimonas, with (R)-ketamine being more potent. These findings suggest that the antidepressant actions of ketamine enantiomers may be partly mediated by restoring gut microbiota, with (R)-ketamine's specific effects on Mollicutes and Butyricimonas potentially explaining its superior efficacy.
Scientific Reports
November 10, 2017
Youge Qu, Chun Yang, Qian Ren et al.
126 citations
In a mouse model of depression induced by chronic social defeat stress, (R)-ketamine, but not the related NMDAR antagonist lanicemine, reversed depression-like behavior and partially restored the composition of gut bacteria, including Bacteroidales, Clostridiales, Ruminococcaceae, and Clostridium. The findings suggest that the antidepressant effects of (R)-ketamine may be partly mediated by its ability to normalize gut microbiota alterations.
The International Journal of Neuropsychopharmacology
August 28, 2019
Jiancheng Zhang, Youge Qu, Lijia Chang et al.
56 citations
A single injection of (R)-ketamine (10 mg/kg) rapidly reversed the loss of dendritic spines in the medial prefrontal cortex and hippocampus of mice that had become susceptible after chronic social defeat stress. Spine density was measured three hours after treatment and was significantly increased in the prelimbic area of the medial prefrontal cortex, the Cornu Ammonis3 region, and the dentate gyrus of the hippocampus. The findings suggest that (R)-ketamine's rapid restoration of spine density in these brain regions may underlie its fast-acting antidepressant effects.
Pharmacology Biochemistry and Behavior
December 5, 2022
Youge Qu, Lijia Chang, Li Ma et al.
42 citations
In mice treated with lipopolysaccharide (LPS) to induce depression-like behavior, both lisuride (a non-hallucinogenic psychedelic analog) and (R)-ketamine (a novel antidepressant) reduced immobility in the forced swimming test and prevented loss of dendritic spine density in the prelimbic region of the medial prefrontal cortex, CA3, and dentate gyrus of the hippocampus. DOI, a hallucinogenic psychedelic with potent 5-HT2AR agonism, did not improve these measures. The findings suggest that the antidepressant-like effect of lisuride is not linked to 5-HT2AR-related psychedelic effects, and that 5-HT2AR may not play a major role in rapid antidepressant actions of psychedelics.
Neurobiology of disease
December 1, 2023
Youge Qu, Akifumi Eguchi, Li Ma et al.
26 citations
Pretreatment with MDMA for 14 days blocked anhedonia-like behavior and reduced synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex of mice exposed to chronic restraint stress. Cutting the subdiaphragmatic vagus nerve (vagotomy) blocked these beneficial effects. The gut microbiome showed differences in α-diversity between groups, and specific microbes varied between vehicle- and MDMA-treated stressed mice. Vagotomy prevented increases in three plasma compounds seen in MDMA-treated stressed mice, and two of those compounds correlated positively with several microbes. The data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve may contribute to MDMA-induced stress resilience.
Neurobiology of disease
September 1, 2024
Lijia Chang, Yan Wei, Youge Qu et al.
22 citations
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
Journal of affective disorders
December 15, 2024
Dan Xu, Guilin Liu, Mingming Zhao et al.
21 citations
A single dose of arketamine (10 mg/kg) improved both depression-like behaviors and demyelination in the corpus callosum of mice exposed to chronic restraint stress. Correlations linked depression-like behaviors with demyelination in that brain region. Blocking the transforming growth factor β1 (TGF-β1) receptor with RepSox prevented arketamine's beneficial effects, while a single intranasal dose of TGF-β1 alone also ameliorated both depression-like behaviors and demyelination. The precise mechanisms remain unclear, but the findings suggest that stress-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and arketamine may act through a TGF-β1-dependent pathway.
Pharmacology, biochemistry, and behavior
December 1, 2023
Guilin Liu, Li Ma, Youge Qu et al.
16 citations
Arketamine, but not the psychedelic drugs DOI or lisuride, produced long-lasting prophylactic effects in mouse models of depression. Male mice pretreated with arketamine six days before an immune challenge (lipopolysaccharide, LPS) showed reduced body weight loss, less spleen enlargement, less immobility in a forced swim test, and higher levels of the synaptic protein PSD-95 in the prefrontal cortex compared to mice pretreated with DOI or lisuride. Similarly, arketamine given one day before seven days of chronic restraint stress prevented increased immobility, restored sucrose preference, and protected PSD-95 expression. DOI and lisuride did not show these protective effects.
Pharmacology, biochemistry, and behavior
May 1, 2024
Li Ma, Akifumi Eguchi, Guilin Liu et al.
11 citations
Pretreatment with the antidepressant arketamine prevented stress-induced body weight loss, increased behavioral despair, decreased sucrose preference, and reduced synaptic protein expression in the prefrontal cortex of male mice exposed to chronic restraint stress. Gut microbiota analysis indicated that arketamine may restore stress-related changes in microbial abundance. Metabolomics identified four blood metabolites altered between stress-exposed and arketamine-pretreated mice. Network analysis linked synaptic proteins in the prefrontal cortex with specific gut microbes and blood metabolites. These findings suggest that the gut-brain axis, including microbial metabolites, may partly underlie the sustained prophylactic effects of arketamine.
Translational psychiatry
July 25, 2023
Li Ma, Long Wang, Youge Qu et al.
Relapse is common in remitted major depressive disorder. Arketamine, an (R)-enantiomer of ketamine, has prophylactic actions in an inflammatory model of depression, but the mechanisms are unclear. In mice, a single injection of arketamine (10 mg/kg) blocked lipopolysaccharide-induced increases in spleen genes of the heme biosynthesis II pathway (Alas2, Fech, Hmbs). Expression of these genes correlated with spleen weight and pro-inflammatory cytokines. Spleens from depressed patients showed higher ALAS2 and FECH expression. Pretreatment with a heme precursor (5-aminolaevulinic acid) worsened inflammation and depression-like behavior, while a heme inhibitor (succinyl acetone) had prophylactic effects. The heme biosynthesis pathway may be a target for preventing relapse.