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

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,...

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Published in:	Biochemical and biophysical research communications Vol. 730; p. 150385
Main Authors:	Liu, Yixiu, Yao, Yilan, Fang, Weiqing, Wang, Xuemeng, Lu, Wen
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 20-10-2024
Subjects:	Animals Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Behavior, Animal - drug effects Depression - drug therapy Depression - metabolism Disease Models, Animal Drug Therapy, Combination Hippocampus Hippocampus - drug effects Hippocampus - metabolism Major depression Male Mice Mice, Inbred C57BL Nitric oxide Nitric Oxide - metabolism Phenols - pharmacology Phenols - therapeutic use Piperidines - pharmacology Piperidines - therapeutic use Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - metabolism Ro25-6981 Stress, Psychological - drug therapy ZL006 Ro25-6981 ZL006 Major depression Nitric oxide Hippocampus
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Summary:	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. •Combined therapy with sub-effective Ro25-6981 and ZL006 show promising in mice.•Combined therapy reduces depressive behaviors in single stressed mice.•Combined therapy ameliorates depressive behaviors in combined stressed mice.•The effects of Combined therapy are dependent on nitric oxide signaling.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-291X 1090-2104 1090-2104
DOI:	10.1016/j.bbrc.2024.150385