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

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.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Song Z,Shen F,Zhang Z,Wu S,Zhu G

doi

10.1016/j.neuropharm.2020.108175

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

108175

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(20)30243-4

journal_volume

174

pub_type

杂志文章

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