Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD.

Autor: Wang TY; Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Weng EF; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan.; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 404333, Taiwan., Hsu YC; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan.; School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan., Shiu LP; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan., Huang TW; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan.; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 404333, Taiwan.; Ph.D. Program for Aging, China Medical University, Taichung, Taiwan., Wu HC; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan.; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 404333, Taiwan., Hong JS; Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Dr., Research Triangle Park, Durham, NC, 27709, USA., Wang SM; Neuroscience and Brain Disease Center, China Medical University, Taichung, Taiwan. wangs@mail.cmu.edu.tw.; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, 404333, Taiwan. wangs@mail.cmu.edu.tw.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Feb 28; Vol. 21 (1), pp. 61. Date of Electronic Publication: 2024 Feb 28.
DOI: 10.1186/s12974-024-03054-2
Abstrakt: There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na + /K + -ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein Delta (CEBPD) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPD in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPD in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPD overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPD-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder.
(© 2024. The Author(s).)
Databáze: MEDLINE
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