Restoring the Redox and Norepinephrine Homeostasis in Mouse Brains Promotes an Antidepressant Response

Effective diagnosis and treatment of major depressive disorder remains a major challenge because diagnostic criteria overlap with other conditions and 50% of patients are resistant to conventional treatments. Emerging evidence has indicated that oxidative stress and reduced norepinephrine are key pathological features of depression. Herein, we constructed a smart organic small-molecule fluorescence-based therapeutic system (Cou-NE-H₂O₂) for the diagnosis and treatment of depression targeted at restoring redox homeostasis and efficiently upregulating norepinephrine in the brain. Utilizing Cou-NE-H₂O₂, we could evaluate the depressive phenotype via the fluorescence monitoring of the redox state in mouse brains. By reducing hydrogen peroxide and continuously increasing norepinephrine, Cou-NE-H₂O₂ elicited a synergistic antidepressant action. Furthermore, we identified that Cou-NE-H₂O₂ can promote the expression of genes such as Grin2a, Drd1, and Fxyd2 related to the cyclic adenosine monophosphate signaling pathway, upregulate glutathione and cysteine to alleviate oxidative stress, and boost neuronal activity by enhancing dopaminergic synapses, ultimately achieving an effective antidepressant response. Taken together, this work provides a new strategy for the evaluation of depression and appropriate treatments and identifies the mechanisms underlying antioxidant and norepinephrine disorders in the brain as potential targets for the development of novel diagnostics and treatments for depression.