1. The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.
- Author
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Zhang X, He T, Wu Z, Wang Y, Liu H, Zhang B, Yang S, Wang D, Huang C, Duan J, Xu X, Xu X, Hashimoto K, Jiang R, Yang L, and Yang C
- Subjects
- Animals, Mice, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Antidepressive Agents metabolism, Hippocampus metabolism, Inflammation metabolism, Lipopolysaccharides pharmacology, Lipopolysaccharides metabolism, Depression metabolism, Ketamine pharmacology, Ketamine therapeutic use, Ketamine metabolism, ADP-ribosyl Cyclase 1 metabolism
- Abstract
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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Chun Yang received research support from Nwha Co. Ltd. Dr. Kenji Hashimoto is the inventor of filed patent applications on “The use of (R)-Ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “(R)-Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, and “(R)-Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder” by the Chiba University. Dr. Hashimoto has also received speakers’ honoraria, consultant fee, or research support from Abbott, Boehringer-Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Dainippon-Sumitomo, Taisho, Otsuka, Murakami Farm and Perception Neuroscience. All the other authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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