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• LPS-induced depression associates with increased CD38 levels in selected brain regions. • Inhibiting CD38 relieves depression-like behaviors via regulating neuroinflammation and synaptic function. • Inhibiting CD38 decreases excessive microglia activation via Sirt1-STAT3-NF-кB signaling pathway. • Neuronal activation in CA3 of hippocampus produces antidepressant effects. • The antidepressant effects of (R)-ketamine are related to decreased CD38 levels. CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development. [ABSTRACT FROM AUTHOR]

The discovery of the robust antidepressant actions of ketamine is regarded as one of the greatest advancements in depression treatment in the past 60 years. Recent findings have provided strong evidence for the presence of bidirectional communication networks between the gastrointestinal tract and the brain in depression. Moreover, increasing evidence supports the antidepressant role of ketamine in regulating the gut microbiome and microbiota-derived molecules; however, the mechanisms underpinning such effects are still ambiguous. This review summarizes the current understanding of the anti-depressant mechanisms of ketamine and its metabolites regarding the bidirectional regulation by microbiota–gut–brain axis. We review the relationship between gut microbiota and the antidepressant mechanisms of ketamine, and discuss the role of stress response, brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effect and neurotransmitters. • Ketamine and its metabolites exert rapid-acting and sustained antidepressant effects. • Gut microbiota contributes to the pathogenesis of depression and the antidepressant actions of ketamine and its metabolites. • The relationship between gut microbiota and the antidepressant effects of ketamine and its metabolites is related to stress response, BDNF expression, neurogenesis, anti-inflammatory effect and neurotransmitters. [ABSTRACT FROM AUTHOR]

Anesthetic ketamine is a racemic mixture containing equal amount of (R)-ketamine and (S)-ketamine. Increasing preclinical data show that (R)-ketamine has a rapid-onset and sustained antidepressant without significant side effects. There are currently many studies on (R)-ketamine, however, the quantity and quality of these studies are unknown. Therefore, we conducted a bibliometric analysis of research on (R)-ketamine from January 2002 to December 2021. We obtained the publications on (R)-ketamine from the Web of Science database during the period. A variety of bibliographic elements were collected, including annual publications, authors, countries/regions, institutions, journals, and keywords. A total of 922 publications were included in this study. Professor Kenji Hashimoto of Chiba University in Japan was the most productively influential author in the field of (R)-ketamine and the authors from United States were the leader in this field. In addition, we found that the antidepressant effect of (R)-ketamine has been a hotspot in very recent years. This study provided a comprehensive analysis of research on (R)-ketamine and highlighted the growing interest in (R)-ketamine and its antidepressant effects. • A total of 922 publications on (R)-ketamine from January 2002 to December 2021 were analyzed. • Professor Kenji Hashimoto of Chiba University was the most productively influential author in the field of (R)-ketamine. • The antidepressant effect of (R)-ketamine has been a hotspot in recent years. [ABSTRACT FROM AUTHOR]

Abstract: A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a–5d and 8a–8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (K i =17nM) and 5-HT2A (K i =0.71nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice. [Copyright &y& Elsevier]