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

Zejie Zuo; Hongyang Zhang; Zhihui Li; Fangfang Qi; Haojie Hu; Junhua Yang; Zhibin Yao

doi:10.1055/a-2429-4023

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2025; 58(03): 117-126
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

Authors

Zejie Zuo

¹Department of Rehabilitation Medicine, The Third Afﬁliated Hospital, Sun Yat-sen University, Guangzhou, China
Hongyang Zhang

²Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
Zhihui Li

²Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
Fangfang Qi

³Department of Neurology, Mayo Clinic, Rochester, MN, USA
Haojie Hu

⁴Department of Psychology, College of Arts and Sciences, New York University, NY, USA
Junhua Yang

⁵Department of Anatomy, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, China
Zhibin Yao

²Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

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

Full Text

References

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