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Combinatorial therapy with sub-effective Ro25-6981 and ZL006 ameliorates depressive-like behavior in single or combined stressed male mice.

Authors :
Liu Y
Yao Y
Fang W
Wang X
Lu W
Source :
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Oct 20; Vol. 730, pp. 150385. Date of Electronic Publication: 2024 Jul 10.
Publication Year :
2024

Abstract

Major depression is a severe neuropsychiatric disorder that poses a significant challenge to health. However, development of an effective therapy for the disease has long been difficult. Here, we investigate the efficacy of a novel combinatorial treatment employing sub-effective doses of Ro25-6981, an antagonist targeting GluN2B-containing NMDA receptors, in conjunction with ZL006, an inhibitor of the PSD95/nNOS, on mouse models of depression. We employed social isolation, chronic restraint stress, or a combination of both to establish a depressed mouse model. Treatment with the drug combination reduced depressive-like behaviors without affecting locomotor activity in mice subjected to social isolation or chronic restraint stress. Furthermore, the combination therapy ameliorated depressive-like behaviors induced by combined stress of chronic restraint followed by social isolation. Mechanistic studies revealed that the combined treatment downregulated the hippocampal nitric oxide level. However, the therapeutic benefits of this combination were negated by the activation of NMDA receptors with a low dose of NMDA or by increasing nitric oxide levels with l-arginine. Moreover, the combinatorial treatment had negligible effects on object memory and contextual fear memory. Our data establish a combined therapy paradigm, providing a potential strategy targeting major depression.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1090-2104
Volume :
730
Database :
MEDLINE
Journal :
Biochemical and biophysical research communications
Publication Type :
Academic Journal
Accession number :
39002200
Full Text :
https://doi.org/10.1016/j.bbrc.2024.150385