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Calpain inhibition ameliorates depression-like behaviors by reducing inflammation and promoting synaptic protein expression in the hippocampus.

Authors :
Song Z
Shen F
Zhang Z
Wu S
Zhu G
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.)

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