Oxidative Stress in Depression: The Link with the Stress Response, Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity

Abstract

Depression is a prevalent, complex, and highly debilitating disease. The full comprehension of this disease is still a global challenge. Indeed, relapse, recurrency, and therapeutic resistance are serious challenges in the fight against depression. Nevertheless, abnormal functioning of the stress response, inflammatory processes, neurotransmission, neurogenesis, and synaptic plasticity are known to underlie the pathophysiology of this mental disorder. The role of oxidative stress in disease and, particularly, in depression is widely recognized, being important for both its onset and development. Indeed, excessive generation of reactive oxygen species and lack of efficient antioxidant response trigger processes such as inflammation, neurodegeneration, and neuronal death. Keeping in mind the importance of a detailed study about cellular and molecular mechanisms that are present in depression, this review focuses on the link between oxidative stress and the stress response, neuroinflammation, serotonergic pathways, neurogenesis, and synaptic plasticity's imbalances present in depression. The study of these mechanisms is important to lead to a new era of treatment and knowledge about this highly complex disease.

Keywords: depression; neurogenesis; neuroinflammation; oxidative stress; reactive oxygen species; serotonin; stress response; synaptic plasticity.

Figure 1

Prooxidant factors such as toxins and pollutants promote high levels of ROS production that are kept at low levels by the antioxidant defenses. However, when ROS production overwhelms antioxidant defenses, harmful effects such as membrane disruption, protein and DNA damage occur, disrupting the normal cell signaling mechanisms and culminating in diseases such as cancer or neurological diseases. Created with BioRender [14].

Figure 2

High levels of ROS promote and are promoted by the stress response, neuroinflammation, and imbalances in neurotransmitter-related pathways and neurogenesis/synaptic plasticity processes. All these features underlie the pathophysiology of depression, being critical in disease development and progression. Upward arrows represent an increment of the represented process. Created with BioRender [14].

Scheme 1

Neurotransmitters of the brain: serotonin (5-HT), noradrenaline (NA)/norepinephrine, and dopamine (DA). 5-HT and NA strongly influence mental behavior patterns, while dopamine is involved in movement.