Antioxidant Biomolecules and Their Potential for the Treatment of Difficult-to-Treat Depression and Conventional Treatment-Resistant Depression

Abstract

Major depression is a devastating disease affecting an increasing number of people from a young age worldwide, a situation that is expected to be worsened by the COVID-19 pandemic. New approaches for the treatment of this disease are urgently needed since available treatments are not effective for all patients, take a long time to produce an effect, and are not well-tolerated in many cases; moreover, they are not safe for all patients. There is solid evidence showing that the antioxidant capacity is lower and the oxidative damage is higher in the brains of depressed patients as compared with healthy controls. Mitochondrial disfunction is associated with depression and other neuropsychiatric disorders, and this dysfunction can be an important source of oxidative damage. Additionally, neuroinflammation that is commonly present in the brain of depressive patients highly contributes to the generation of reactive oxygen species (ROS). There is evidence showing that pro-inflammatory diets can increase depression risk; on the contrary, an anti-inflammatory diet such as the Mediterranean diet can decrease it. Therefore, it is interesting to evaluate the possible role of plant-derived antioxidants in depression treatment and prevention as well as other biomolecules with high antioxidant and anti-inflammatory potential such as the molecules paracrinely secreted by mesenchymal stem cells. In this review, we evaluated the preclinical and clinical evidence showing the potential effects of different antioxidant and anti-inflammatory biomolecules as antidepressants, with a focus on difficult-to-treat depression and conventional treatment-resistant depression.

Keywords: exosomes; major depressive disorder; mesenchymal stem cells; neuroinflammation; oxidative stress; plant extracts.

Figure 1

Endogenous and exogenous functional components of the antioxidant system in humans. The figure shows antioxidant molecules organized according to its origin that can be endogenous, which are synthetized by the organism, or exogenous, which have to be consumed in the diet. In addition to their source (endogenous or exogenous), antioxidants may be classified according to their antioxidant action into primary, secondary, and tertiary. Primary antioxidants are chain-breaking antioxidants that accept free radicals terminating the propagation of oxidative reactions and transform free radical species into more stable and less reactive products. Secondary antioxidants are radical scavenging molecules, and they have a preventive role in suppressing chain reaction initiation. Tertiary antioxidants are enzyme systems that can repair biomolecules that have been damaged by oxidation. Additionally, antioxidant action could be direct or indirect. Indirect antioxidants enhance many of the direct primary and secondary antioxidants. Finally, antioxidants could be enzymes or non-enzymatic molecules. SOD: superoxide dismutase, CAT: catalase, GPx: glutathione peroxidase, Trx: thioredoxin, GR: glutathione reductase, GSH: reduced glutathione, G6PD: glucose 6 phosphate dehydrogenase, GST: glutathione S transferase.

Figure 2

Interaction between oxidative stress and neuroinflammation at the onset of major depressive disorder. Figure shows that psychological and/or physical stressors can trigger the pathophysiology associated with major depression. Once the limit of the brain’s antioxidant capacity has been exceeded, oxidative stress prevails, inducing neuroinflammation and the deterioration of brain cells, which over time leads to the induction of the main phenotype associated with major depressive disorder. Red rays show the possible targets of plant-derived extracts and acellular products derived from mesenchymal stem cells.