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Pharmacopsychiatry
DOI: 10.1055/a-2429-4023
Original Paper

Activation of Hippocampal Neuronal NADPH Oxidase NOX2 Promotes Depressive-Like Behaviour and Cognition Deficits in Chronic Restraint Stress Mouse Model

Zejie Zuo
1   Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
,
Hongyang Zhang
2   Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
,
Zhihui Li
2   Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
,
Fangfang Qi
3   Department of Neurology, Mayo Clinic, Rochester, MN, USA
,
Haojie Hu
4   Department of Psychology, College of Arts and Sciences, New York University, NY, USA
,
Junhua Yang
5   Department of Anatomy, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
,
Zhibin Yao
2   Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
› Author Affiliations Funding This research was funded by the Guangzhou Science and Technology planning project (202201020413, 2023A04J1099) and the National Science Foundation of China (81801058).
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Abstract

Background Nicotinamide adenosine dinucleotide phosphate oxidases (NOX) play important roles in mediating stress-induced depression. Three NOX isotypes are expressed mainly in the brain: NOX2, NOX3 and NOX4. In this study, the expression and cellular sources of these NOX isoforms was investigated in the context of stress-induced depression.

Methods Chronic restraint stress (CRS)-induced depressive-like behaviour and cognitive deficits were evaluated by tail suspension tests, forced swimming tests and the Morris water maze test. Hippocampal NOX expression was determined by immunofluorescence staining and western blotting. The hippocampal levels of the brain-derived neurotrophic factor (BDNF) mRNA were determined via quantitative real-time –polymerase chain reaction. Glucocorticoid levels in the hippocampus were measured using ELISA kits.

Results In the mouse CRS model, a significant increase in NOX2 expression was observed in the hippocampus, whereas no significant changes in NOX3 and NOX4 expression were detected. Next, NOX2 expression was primarily localised to neurons (NeuN+) but not microglia (Iba-1+) or astrocytes (GFAP+). Treatment with gp91ds-tat, a specific NOX2 inhibitor, effectively mitigated the behavioural deficits induced by CRS. The decreased expression of the BDNF mRNA in the hippocampus of CRS mice was restored upon gp91ds-tat treatment. A positive correlation was identified between neuronal NOX2 expression and serum glucocorticoid levels.

Conclusions Our study indicated that neuronal NOX2 may be a critical mediator of depression-like behaviours and spatial cognitive deficits in mice subjected to CRS. Blockade of NOX2 signalling may be a promising therapeutic strategy for depression.

Keywords

chronic restraint stress - depression-like behaviour - cognitive deficits - NOX - BDNF


Publication History

Received: 25 June 2024
Received: 05 September 2024

Accepted: 20 September 2024

Article published online:
15 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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