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Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus.
- Source :
-
Neuropharmacology [Neuropharmacology] 2020 Sep 01; Vol. 174, pp. 108175. Date of Electronic Publication: 2020 May 31. - Publication Year :
- 2020
-
Abstract
- Protease activity correlates with depressive or suicidal behaviors, with calpain activation being especially implicated in depression-like behaviors. However, the role of calpain in depression-like behaviors is currently unknown. In this study, the lipopolysaccharide (LPS) - and chronic unpredictable mild stress (CUMS)-induced depression models were used to evaluate the antidepressant effects of calpain inhibitors. Potential mechanisms were determined using pharmacological and biochemical methods. We found that i. p. injection of a calpain inhibitor, calpeptin, prevented LPS-induced depression-like behaviors, activation of astrocytes, inflammation, and reduction of synaptic protein expression levels. LPS injection (i.p.) promoted calpain activity, which degraded suprachiasmatic nucleus circadian oscillatory protein (SCOP). This led to the activation of ERK and nuclear translocation of nuclear factor kappa-B (NF-κB), the promotion of cytokine release, and the reduction of Arc, and PSD95 expression in the hippocampus. In contrast, i. p. injection of calpeptin blocked these changes. Furthermore, intraventricular injection of calpain inhibitor (PD150606) or an ERK inhibitor ameliorated the LPS-induced depression-like behaviors. Administration of calpeptin also remedied CUMS-induced depression-like behaviors, degradation of SCOP, activation of astrocytes, and reduction of synaptic protein expression levels. Finally, we also demonstrated that memantine, an N-methyl-d-aspartic acid (NMDA) receptor antagonist blocks LPS-induced degradation of SCOP. Together, our results show that calpain inhibition ameliorates depression-like behaviors, probably by reducing inflammation and promoting synaptic protein expression in the hippocampus.<br />Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antidepressive Agents pharmacology
Brain-Derived Neurotrophic Factor biosynthesis
Brain-Derived Neurotrophic Factor genetics
Calpain antagonists & inhibitors
Cytoskeletal Proteins biosynthesis
Cytoskeletal Proteins genetics
Depression chemically induced
Depression drug therapy
Dipeptides pharmacology
Dipeptides therapeutic use
Disks Large Homolog 4 Protein biosynthesis
Disks Large Homolog 4 Protein genetics
Gene Expression
Glycoproteins pharmacology
Hippocampus drug effects
Inflammation chemically induced
Inflammation drug therapy
Inflammation metabolism
Intracellular Signaling Peptides and Proteins genetics
Lipopolysaccharides toxicity
Male
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins biosynthesis
Nerve Tissue Proteins genetics
Presynaptic Terminals drug effects
Presynaptic Terminals metabolism
Antidepressive Agents therapeutic use
Calpain metabolism
Depression metabolism
Glycoproteins therapeutic use
Hippocampus metabolism
Intracellular Signaling Peptides and Proteins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 174
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32492450
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2020.108175