COVID-19, Oxidative Stress, and Neuroinflammation in the Depression Route

Abstract

COVID-19 is associated with oxidative stress, peripheral hyper inflammation, and neuroinflammation, especially in individuals with a more severe form of the disease. Some studies provide evidence on the onset or exacerbation of major depressive disorder (MDD), among other psychiatric disorders due to COVID-19. Oxidative stress and neuroinflammation are associated conditions, especially in the more severe form of MDD and in refractoriness to available therapeutic strategies. Inflammatory cytokines in the COVID-19 hyper inflammation process can activate the hypothalamic-pituitary-adrenal (HPA) axis and the indoleamine-2,3-dioxygenase (IDO) enzyme. IDO activation can reduce tryptophan and increase toxic metabolites of the kynurenine pathway, which increases glial activation, neuroinflammation, toxicity, and neuronal death. This review surveyed a number of studies and analyzed the mechanisms of oxidative stress, inflammation, and neuroinflammation involved in COVID-19 and depression. Finally, the importance of more protocols that can help elucidate the interaction between these mechanisms underlying COVID-19 and MDD and the possible therapeutic strategies involved in the interaction of these mechanisms are highlighted.

Keywords: COVID-19; Glial activation; Major depressive disorder; Neuroinflammation; Oxidative stress.

Fig. 1

Invasion pathways of SARS-CoV-2, neuroinflammation, and MDD. SARS-CoV-2 can invade the body through various pathways, thus causing systemic inflammation. The virus uses enzyme ACE2 as an entry receptor for cell invasion, resorting to TMPRSS2 to initiate its S protein of ACE2. The ACE2 expression is known in human blood vessel endothelial and microvasculature cells. Thus, invasion by the virus causes systemic inflammation, whose main characteristic is the activation of the cytokine production cascade, called cytokine storm. This systemic inflammation compromises permeability of the blood–brain barrier (BBB), making it unstable. With this, the brain is flooded with pro-inflammatory factors, and the passage is free for SARS-CoV-2 neuroinvasion, which can be through infected leukocytes. This process will activate microglia and astrocytes, which will release more pro-inflammatory factors. From this, neuroinflammation propagates, which is positively associated with MDD. The virus can also reach the CNS through the circumventricular organs, midline structures around the third and fourth ventricles, which the BBB does not protect. Another gateway is through the olfactory epithelium, in which the virus propagates through the olfactory nerve, crossing the cribriform lamina and reaching the olfactory bulb in the CNS. This way is retrograde dissemination, through trans-synaptic transfer, using endocytosis and exocytosis processes of vesicles containing the virus, with subsequent axonal transport to the neuronal cell bodies. The images were extracted from the BioRender app

Fig. 2

SARS-CoV-2, ACE2 and oxidative stress. SARS-CoV-2 can modulate oxidative stress and the inflammatory response, both processes that directly contribute to COVID-19 severity. Coming from the liver, angiotensinogen is cleaved by renin, and released by the kidneys to angiotensin I (Ang I), which is then converted to angiotensin II (Ang II) through the action of ACE. Ang II is a potent vasoconstrictor, which uses the AT1 receptor to signal the NF-κB transcription factor, which results in the activation of NADPH oxidase (NOX), an essential source of ROS production. Ang II will be converted to angiotensin (1–7) through ACE2. However, SARS-CoV-2 uses ACE2 for cell invasion, promoting a decrease in the expression of this enzyme and suppressing its proteolytic activity. With this enzyme’s local or systemic depletion, there is an increase in the level of Ang II and, consequently, a more significant induction of ROS production via NOX in endothelial cells, triggering mitochondrial oxidative stress and endothelial dysfunction. The images were extracted from the BioRender app

Fig. 3

COVID-19 and glial activation by the kynurenine pathway — MDD route. SARS-CoV-2 induces a cytokine storm. Pro-inflammatory cytokines such as INF-α, TNF-α, IFN-y, and IL-6 stimulate the action of IDO, which, together with TDO, is responsible for converting tryptophan into kynurenine. Proportionally, with the increased action of IDO, there is an increase in the conversion of available tryptophan into kynurenine. With that, there is greater kynurenine pathway activity and lower tryptophan bioavailability for the serotonin pathway. Another action of pro-inflammatory cytokines is to increase the action of enzymes in the QA transformation chain in the microglia. KMO, KYNU, and 3-HAO have their activities increased, thus promoting greater conversion of KYN into its end product: QA. This neurotoxic metabolite can positively affect ROS production, promoting oxidative stress. Neuroinflammation and oxidative stress result in brain damage and in major depressive disorder (MDD). The images were extracted from the BioRender app