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.
European journal of pharmacology
December 15, 2024
Ming-Ming Zhao, Ting-Ting Zhu, Dan Xu et al.
14 citations
Arketamine, the (R)-enantiomer of ketamine, reduces damage to the myelin sheath and promotes its repair in the brains of mice treated with cuprizone, a chemical that induces demyelination. The beneficial effects occur through a mechanism dependent on transforming growth factor β1 (TGF-β1). Blocking the TGF-β1 receptor with RepSox prevented arketamine's protective effects. Directly administering TGF-β1 intranasally also reduced demyelination and enhanced remyelination in the corpus callosum. These findings suggest that arketamine's effects on myelin repair rely on TGF-β1 signaling, pointing to potential therapeutic targets for demyelinating diseases like multiple sclerosis.
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.
European journal of pharmacology
March 15, 2025
Mingming Zhao, Akifumi Eguchi, Rumi Murayama et al.
6 citations
Intermittent MDMA administration (10 mg/kg, three times weekly for 6 weeks) reduced demyelination in the corpus callosum of mice treated with cuprizone, a chemical that induces myelin loss. The effect appears linked to changes in gut bacteria and metabolites, including β-D-allose, L-sorbose, and carnitine, which correlated negatively with specific microbes such as Romboutsia. These findings suggest MDMA may influence brain demyelination through the gut-brain axis, though further research is needed to clarify the roles of gut microbiota and metabolites.
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
November 30, 2025
Xiayun Wan, Akifumi Eguchi, Rumi Murayama et al.
5 citations
Intermittent doses of MDMA (10 mg/kg three times per week for six weeks) increased whole-body and femoral bone mineral density in ovariectomized mice, compared with vehicle. The treatment shifted bone-remodeling markers toward an antiresorptive profile—lower RANKL and higher osteoprotegerin. Gut microbiota profiling showed reduced Clostridia and enriched Bacilli, and untargeted metabolomics revealed a marked decrease in plasma β-D-allose, a metabolite linked to Lactobacillus johnsonii. These findings suggest that intermittent MDMA may mitigate bone density loss after ovariectomy, potentially through remodeling of a gut microbiota–bone axis. Causal microbial and metabolic mediators remain to be defined.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2025
Ting-Ting Zhu, Ming-Ming Zhao, Dan Xu et al.
5 citations
Postoperative cognitive dysfunction (POCD) involves declines in memory, attention, and executive abilities after surgery, with no effective drugs available. In a mouse model of POCD, a single injection of arketamine (10 mg/kg) improved cognitive function and reduced demyelination in the corpus callosum. Blocking TGF-β receptor 1 with RepSox (10 mg/kg) prevented these benefits, while intranasal TGF-β1 (3.0 μg/kg) alone alleviated cognitive impairments and demyelination. The findings indicate arketamine acts through a TGF-β1-dependent mechanism, suggesting it as a potential treatment for POCD.
Progress in neuro-psychopharmacology & biological psychiatry
March 20, 2025
Yong Yue, Xiayun Wan, Guilin Liu et al.
4 citations
The gut-brain axis, specifically the subdiaphragmatic vagus nerve, is critical for MDMA's effects on the oxytocin system in rats. Cutting this nerve (subdiaphragmatic vagotomy) lowered baseline oxytocin levels in the blood and reduced oxytocin expression in the paraventricular and supraoptic nuclei of the hypothalamus. It also dampened MDMA-induced increases in blood oxytocin and the expression of oxytocin and c-Fos in those brain regions. The findings suggest the vagus nerve mediates brain-body communication that underlies MDMA's pharmacological actions on oxytocin.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2025
Dan Xu, Akifumi Eguchi, Rumi Murayama et al.
4 citations
Repeated oral administration of MDMA (10 mg/kg/day for 14 days) to male rats significantly altered gut microbiota composition in the small intestine, cecum, and colon, with distinct effects in each region. Analysis of microbial functional capabilities indicated shifts in several metabolic pathways. Untargeted metabolomics showed that MDMA changed levels of two metabolites in the colon—ferulic acid and methylmalonic acid—without affecting levels in blood, small intestine, or cecum. Methylmalonic acid levels in the colon positively correlated with the bacteria Lawsonibacter and Oscillibacter. These results suggest that repeated MDMA treatment can modify gut microbiota across intestinal regions, which may contribute to its pharmacological effects.
Pharmacology, biochemistry, and behavior
December 1, 2024
Guilin Liu, Li Ma, Akemi Sakamoto et al.
4 citations
A single dose of arketamine, the (R)-enantiomer of ketamine, reduced depression-like behavior and inflammation in mice given lipopolysaccharide (LPS), a bacterial toxin that triggers an immune response. Arketamine also prevented these effects when given six days before LPS. LPS lowered the proportion of γδ T cells in the spleen, and arketamine reversed this change and reduced spleen enlargement and interleukin-6 levels. Blocking γδ T cells with an antibody eliminated arketamine's benefits, suggesting these immune cells are essential for its effects. The findings indicate splenic γδ T cells may be a new target for treating inflammation-related depression.
Translational Psychiatry
May 20, 2026
Xin Ding, Rumi Murayama, Yi Cai et al.
1 citation
The drug combination KarXT (xanomeline plus trospium) reverses cognitive deficits caused by phencyclidine (PCP) in adult male mice, and this effect is linked to changes in gut and lung microbiota. PCP disrupted recognition memory and caused region-specific imbalances in microbes, especially in the small intestine and cecum. KarXT restored memory and normalized several bacterial species elevated by PCP, including Bacteroides fragilis and Veillonella ratti. Restoration of certain lung and gut microbes correlated with improved memory. The findings suggest that KarXT's cognitive benefits involve microbial modulation, which may guide efforts to reduce gastrointestinal side effects in muscarinic therapies for schizophrenia.
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
May 31, 2026
Yong Yue, Yi Cai, Rumi Murayama et al.
Gut bacteria contribute to baseline central oxytocin signaling in rats, but are not necessary for the acute oxytocin release triggered by MDMA. Male rats given broad-spectrum antibiotics for seven days showed enlarged ceca, confirming microbiome disruption, yet maintained stable body weight. Baseline oxytocin expression in the paraventricular and supraoptic nuclei of the hypothalamus was significantly reduced after antibiotic treatment, while peripheral oxytocin levels remained unchanged. MDMA administration increased central oxytocin expression similarly in both antibiotic-treated and control rats, and MDMA-induced peripheral oxytocin levels also did not differ between groups. The findings indicate that gut microbiota help maintain central oxytocin under normal conditions but are not required for MDMA's oxytocin-activating effects.