How Oxidative Stress Induces Depression?

Abstract

Depression increasingly affects a wide range and a large number of people worldwide, both physically and psychologically, which makes it a social problem requiring prompt attention and management. Accumulating clinical and animal studies have provided us with substantial insights of disease pathogenesis, especially central monoamine deficiency, which considerably promotes antidepressant research and clinical treatment. The first-line antidepressants mainly target the monoamine system, whose drawbacks mainly include slow action and treatment resistant. The novel antidepressant esketamine, targeting on central glutamatergic system, rapidly and robustly alleviates depression (including treatment-resistant depression), whose efficiency is shadowed by potential addictive and psychotomimetic side effects. Thus, exploring novel depression pathogenesis is necessary, for seeking more safe and effective therapeutic methods. Emerging evidence has revealed vital involvement of oxidative stress (OS) in depression, which inspires us to pursue antioxidant pathway for depression prevention and treatment. Fully uncovering the underlying mechanisms of OS-induced depression is the first step towards the avenue, thus we summarize and expound possible downstream pathways of OS, including mitochondrial impairment and related ATP deficiency, neuroinflammation, central glutamate excitotoxicity, brain-derived neurotrophic factor/tyrosine receptor kinase B dysfunction and serotonin deficiency, the microbiota-gut-brain axis disturbance and hypothalamic-pituitary-adrenocortical axis dysregulation. We also elaborate on the intricate interactions between the multiple aspects, and molecular mechanisms mediating the interplay. Through reviewing the related research progress in the field, we hope to depict an integral overview of how OS induces depression, in order to provide fresh ideas and novel targets for the final goal of efficient treatment of the disease.

Advancements Exploring Major Depressive Disorder: Insights on Oxidative Stress, Serotonin Metabolism, BDNF, HPA Axis Dysfunction, and Pharmacotherapy Advances

“…Furthermore, it has been demonstrated that antidepressants have antioxidant properties, and antioxidants exhibit antidepressant effects. For instance, fluoxetine and citalopram enhanced SOD activity and ascorbic acid levels, reducing malondialdehyde in MDD patients [21,29]. Research conducted on cell lines further supports the link between oxidative stress and depression.…”

“…When combined with a decrease in antioxidant defenses, these mechanisms support the role of oxidative stress as a key player in depression [20]. Also, research reported elevated levels of peroxidation biomarkers combined with reduced antioxidant activity in the plasma and serum of individuals with MDD [21,24,25]. Targeting hypoxia-related pathways may also be a promising tool for depressive disorders in the context of mitigating high-oxidative stress levels, enhanced by hypoxia [8,26].…”

“…This makes oxidative stress an important cause of neurodegeneration and a key factor in MDD. Addressing these changes with suitable antioxidants could be an effective strategy for treating MDD [15,20,21].…”

“…Treatment with edaravone enhanced cell viability and decreased ROS levels, likely attributable to its free radical-scavenging characteristics [27]. Various studies have also observed reductions in antioxidant levels in both depressed patients and animal models of depression [21,28]. Furthermore, it has been demonstrated that antidepressants have antioxidant properties, and antioxidants exhibit antidepressant effects.…”

Longitudinal association between possible sarcopenic obesity and depression among the middle-aged and the elderly: The evidence from CHARLS

“…Signi cant attention has been paid to SO as it seems more harmful to health than obesity or sarcopenia alone [5]. Insulin resistance, in ammation, oxidative stress, and hormonal changes related to sarcopenia and obesity could be the pathogenesis of depression [6][7][8]. According to previous studies, obesity and sarcopenia alone were associated with depression.…”