Effects of arketamine on depression-like behaviors and demyelination in mice exposed to chronic restrain stress: A role of transforming growth factor-ß1.

BACKGROUND: Chronic restrain stress (CRS) induces depression-like behaviors and demyelination in the brain; however, the relationship between these depression-like behaviors and demyelination remains unclear. Arketamine, the (R)-enantiomer of ketamine, has shown rapid antidepressant-like effects in CRS-exposed mice. METHODS: We examined whether arketamine can improve both depression-like behaviors and demyelination in the brains of CRS-exposed mice. Additionally, we investigated the role of transforming growth factor ß1 (TGF-ß1) in the beneficial effects of arketamine. RESULTS: A single dose of arketamine (10 mg/kg) improved both depression-like behavior and demyelination in the corpus callosum of CRS-exposed mice. Correlations were found between depression-like behaviors and demyelination in this region. Furthermore, pretreatment with RepSox, an inhibitor of TGF-ß1 receptor, significantly blocked the beneficial effects of arketamine on depression-like behaviors and demyelination in CRS-exposed mice. Finally, a single intranasal administration of TGF-ß1 ameliorated both depression-like behaviors and demyelination in CRS-exposed mice. LIMITATIONS: The precise mechanisms by which TGF-ß1 contributes to the effects of arketamine remain unclear. CONCLUSIONS: These data suggest that CRS-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and that arketamine can mitigate these changes through a TGF-ß1-dependent mechanism.

A role of gut-brain axis on prophylactic actions of arketamine in male mice exposed to chronic restrain stress.

The gut-brain axis, which includes gut microbiota and microbiome-derived metabolites, might be implicated in depression. We reported the sustained prophylactic effects of a new antidepressant arketamine in chronic restrain stress (CRS) model of depression. In this study, we investigated the role of gut-brain axis on the prophylactic effects of arketamine in the CRS (7 days) model. Pretreatment with arketamine (10 mg/kg, 1 day prior to the CRS onset) significantly prevented CRS-induced body weight loss, increased immobility time of forced swimming test, decreased sucrose preference of sucrose preference test, and reduced expressions of synaptic proteins (GluA1 and PSD-95) in the prefrontal cortex (PFC) in the male mice. Gut microbiota analysis showed that pretreatment with arketamine might restore altered abundance of gut microbiota in CRS-exposed mice. An untargeted metabolomics analysis revealed four metabolites (e.g., L-leucine, N-acetyl-l-glutamine, 2-(2,4-dichlorophenyl)-3-[4-(dimethylamino)phenyl]acrylonitrile, L-threonine amide) that were altered between control and CRS group; however, there were found to be altered between the saline + CRS group and the arketamine + CRS group. Network analysis demonstrated correlations among synaptic proteins in the PFC and certain microbiota, and blood metabolites. These findings suggest that gut-brain axis, including its metabolites, might partially contribute to the persistent prophylactic effects of arketamine in the CRS model.

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.

Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT2AR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression.

Effects of Tyrosine Kinase Inhibitors on Blood Pressure in Patients with Unresectable or Advanced Recurrent Renal Cell Carcinoma-Bayes-Mixed Treatment Comparison Meta-Analysis.

Although cytokine therapy has been a common drug therapy for renal cell carcinoma for long since the 1980s, the evidence for the rationale of this therapy has been limited. Currently, 7 molecular targeted drugs(ie, sorafenib, sunitinib, axitinib, pazopanib, cabozantinib, everolimus, and temsirolimus)are available in Japan. Among these molecular targeted drugs, we clinically evaluated 5 tyrosine kinase inhibitors(ie, sorafenib, sunitinib, axitinib, pazopanib, and cabozantinib)in terms of their effects on blood pressure and the response rate by Bayes-mixed treatment comparison meta-analysis(Bayes- MTC analysis)to develop the decision-making model for the optimal treatment selection. Cabozantinib and axitinib exerted the greatest effect on blood pressure, and their probability of affecting blood pressure was 1.7 to 2 times higher than the probability of sunitinib. Among the 5 tyrosine kinase inhibitors, the effects of sunitinib and sorafenib on blood pressure were small. According to the results of clinical trials in Japan, hypertension was observed in 27.5% of patients treated with sorafenib, 51.0% with sunitinib, and 75.7% with axitinib. Our analysis also showed similar results. This study demonstrated that Bayes-MTC analysis is a useful tool enabling not only direct evaluation but also indirect evaluation.