COVID-19 and neurological sequelae: Vitamin D as a possible neuroprotective and/or neuroreparative agent

Abstract

SARS-CoV-2, the etiological agent of the current COVID-19 pandemic, belongs to a broad family of coronaviruses that also affect humans. SARS-CoV-2 infection usually leads to bilateral atypical pneumonia with significant impairment of respiratory function. However, the infectious capacity of SARS-CoV-2 is not limited to the respiratory system, but may also affect other vital organs such as the brain. The central nervous system is vulnerable to cell damage via direct invasion or indirect virus-related effects leading to a neuroinflammatory response, processes possibly associated with a decrease in the activity of angiotensin II converting enzyme (ACE2), the canonical cell-surface receptor for SARS-CoV-2. This enzyme regulates neuroprotective and neuroimmunomodulatory functions and can neutralize both inflammation and oxidative stress generated at the cellular level. Furthermore, there is evidence of an association between vitamin D deficiency and predisposition to the development of severe forms of COVID-19, with its possible neurological and neuropsychiatric sequelae: vitamin D has the ability to down-modulate the effects of neuroinflammatory cytokines, among other anti-inflammatory/immunomodulatory effects, thus attenuating harmful consequences of COVID-19. This review critically analyzes current evidence supporting the notion that vitamin D may act as a neuroprotective and neuroreparative agent against the neurological sequelae of COVID-19.

Keywords: COVID-19; Neurodegeneration; Neuroinflammation; Neuroreparation; Sequelae; Vitamin D.

Graphical abstract

Fig. 1

Schematic representation of the effects of 1,25(OH)2D on the renin-angiotensin-aldosterone system. SARS-CoV-2 uses the ACE2 as the main receptor entry site and downregulates ACE2 in the lungs. This causes the accumulation of angiotensin II, which causes inflammation and apoptosis in the lungs and systemic vasoconstriction by interacting with the AT1 receptor, leading to COVID-related complications including ARDS, myocarditis, and cardiac injury. 1,25(OH)2D inhibits renin and ACE and induces the expression of ACE2 in the lungs, thereby reducing the accumulation of angiotensin II. Inhibition of renin expression may also result in decreased flux of angiotensin I to angiotensin-(1–9), thereby mitigating bradykinin storm. Additionally, 1,25(OH)2D may inhibit ACE2 expression in the renal tubular cells, which is thought to be protective against COVID-associated kidney injury by reducing the viral direct cytopathic effects on the cell. 1,25(OH)2D = 1,25-dihydroxyvitamin D; ACE = angiotensin converting enzyme; ACE2 = angiotensin converting enzyme 2; ARDS = acute respiratory distress syndrome; AT1receptor = angiotensin II type 1 receptor; COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory distress syndrome coronavirus 2.

Fig. 2

Schematic representation of paracrine and intracrine function of vitamin D and its metabolites and actions of 1,25-dihydroxyvitamin D on the innate and adaptive immune systems. 1,25(OH)2D = 1,25-dihydroxyvitamin D; 25(OH)D = 25-hydroxyvitamin D; IFN-Ƴ = interferon-Ƴ; IL = interleukin; MHC = membrane histocompatibility complex; TH1 = T helper 1; TH2 = T helper 2; TH17 = T helper 17; Treg = regulatory T cell; TLR2 = toll-like receptor 2; TLR4 = toll-like receptor 4; TNF-α = tumor necrosis factor- α.

Fig. 3

SARS-CoV-2 invasion leads to a neuroinflammatory and neurodegenerative process due to a potentially connected reduction in the angiotensin II converting enzyme (ACE2) activity. Vitamin D controls this enzyme, which has neuroprotective and neuroimmunomodulatory activities. In addition, vitamin D, among other anti-inflammatory/immunomodulatory actions, can down-modulate the effects of neuroinflammatory cytokines, reducing COVID-19's detrimental effects. This research supported the hypothesis that vitamin D may function as a neuroprotective and neuroreparative agent against the neurological consequences of COVID-19. Signs (+) or (−) mean stimulation and inhibition, respectively. Signs (+) or (−) mean stimulation and inhibition respectively. 1,25(OH)2D = 1,25-dihydroxyvitamin D; ACE = angiotensin converting enzyme; ACE2 = angiotensin converting enzyme 2; VRD = vitamin D receptor; IL-34 = interleukin 34; IL-4 = interleukin 4; IL-10 = interleukin 10; TGF-β = transforming growth factor-beta; ROS = reactive oxygen species; iNOS = inducible nitric oxide synthase; GDNF = glial cell-derived neurotrophic factor; NGF = neurotrophin nerve growth factor; GSH = reduced glutathione; BDNF = brain-derived neurotrophic factor.