Neurocovid,Neuroinflammation,and Nuclear Factor-κB: The Role for Micronutrients

The coronavirus disease 2019 (COVID-19) is a viral disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Approximately, 80% of hospitalized COVID-19 patients develop a wide range of neurologic complications including encephalopathy, anosmia, ischemic stroke, intracerebral hemorrhage, and neurodegenerative diseases. ¹ According to analysis from the Global Consortium Study of Neurologic Dysfunction in COVID-19, patients with clinically diagnosed neurologic symptoms have six times higher risk of mortality than those without the neurologic problems. ²

Neurologic symptoms in COVID-19 patients arise because of cytokine storm and inflammation in the brain that is mediated through nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathway. ¹ NF-κB is a major signaling pathway involved in neuroinflammation, which is associated with greater severity of COVID-19. Although acute inflammation in response to infection may be beneficial, chronic inflammation likely leads to tissue injury and is associated with neurodegenerative disorders such as Alzheimer's disease (AD). Emerging evidence indicates that the activity of NF-κB is significantly augmented during the neurodegenerative process.

In addition, neuroinflammation was detected in >80% of COVID-19 patients who developed neurologic symptoms such as headache, mental confusion, olfactory dysfunction (hyposmia), delirium, and rarely coma. Interestingly, early onset AD with hyposmia has also been observed in neuropathology assessments of COVID-19 patients. In addition, AD type II astrocytosis has been reported in neurologic studies of COVID-19 patients. ³

SARS-CoV-2 has a strong affinity to angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in the hippocampus, cortex, amygdala, and hypothalamus. ⁴ In addition, ACE2 is expressed in glia and neurons, which makes both brain cell types more susceptible to SARS-CoV-2 infection. ⁴ ACE2 triggers inflammation through activation of the NF-κB signaling pathway. ¹ The NF-κB subunits are expressed in glia and neurons derived from AD brains. There is robust evidence that NF-κB is linked to AD, suggesting that inhibiting NF-κB putatively decreases AD risk.

SARS-CoV spike protein binds with host ACE2, which allows the virus to enter host cells. Viral single-stranded RNA virus activates the Toll-like receptors (TLRs), which activate IκB kinase, resulting in the phosphorylation of the cytoplasmic inhibitor factor IκBα, and ultimately its degradation. ¹ Later, NF-κB subunits are separated from IκBα and translocate into the nucleus to induce harmful cytokine responses.

Excessive NF-κB activation triggers the production of proinflammatory cytokines and inflammation after SARS-CoV infection. Hence NF-κB suppressors are promising as potential therapeutic agents in SARS-CoV sequalae including neurocovid. ¹ Inhibition of the NF-κB signaling pathway led to a reduction in inflammation in SARS-CoV–infected mice and significantly increased survival rate after SARS-CoV infection. ⁵

Therefore, understanding how the NF-κB signaling pathway regulates inflammatory responses may aid in the development of novel therapeutics that inhibit the NF-κB pathway to diminish the cytokine storm and ultimately reduce disease severity including neurocovid. The NF-κB pathway is a redox-sensitive transcription factor, which becomes activated by oxidative stress.

Inhibiting an overactive NF-κB pathway may be important in recovery from neurocovid and several essential micronutrients appear to be important in this regard. Conceivably such homeostasis may be accomplished with restoration of adequate, but not excessive, stores of vitamin D, magnesium, zinc, and selenium.

Vitamin D has been shown in vitro to inhibit the activation of NF-κB through a mechanism that included reduced activation of the tissue factor gene. 1,25 Dihydroxy vitamin D is an essential cofactor for the activation of genes responsible for the response to viruses and bacteria including COVID-19. ⁶ It is also crucial for the modulation of inflammation including neuroinflammation, and deficiency of this factor is associated with several neuroinflammatory disorders including Parkinson's disease and AD. Moreover COVID-19 infection is more likely to occur in vitamin D deficient individuals even when correcting for other conditions. ⁷

The vitamin D deficient group was 14 times more likely to have severe manifestations of COVID-19 infection than those persons who had adequate vitamin D. What is not yet known is the percentage of neurocovid patients who are vitamin D deficient, but this should be readily ascertained.

Magnesium has a related ability to downregulate NF-κB as free intracellular magnesium and helps modulate immune function since the mineral is essential for the proper functioning of natural killer cells and CD8⁺ T cells. ⁸ Magnesium is a required cofactor for vitamin D to function properly. Deficiencies of either substance may lead to immune dysregulation including within the central nervous system's microglial cells whose activation is highly likely a component of neurocovid.

Zinc's relationship with NF-κB activation varies with cell lineage. In those cells subjected to oxidative stress such as astrocytes and microglial cells of the central nervous system, zinc deficiency may promote NF-κB activation while inhibiting the anti-inflammatory effects of other regulatory mechanisms such as proliferator-activated receptor γ. ⁹ Even while the restoration of an adequate supply of zinc is likely especially important in COVID-19 including neurocovid, it is imperative to avoid excessive supplementation that can also impair host defense mechanisms and be neurotoxic. This narrow zone of efficacy is also true with other mineral cofactors important in immune function such as selenium.

Selenium is a major component of the selenoproteins that are major antioxidants including glutathione and glutathione reductase. Defects in these proteins and selenoprotein S can lead to elevation in the inflammatory cytokines that contribute to NF-κB enhancement, and in some studies, both human and animal, selenium supplementation reduces cytokine activation. ¹⁰

In the urgent pursuit of effective therapies for neurocovid, the roles of deficiencies of vitamin D, magnesium, zinc, and selenium in COVID-19 disease should not be overlooked. These nutrients are essential for the proper functioning of the immune system in several aspects including those pertaining to NF-κB.

Thiamine is likely another micronutrient essential for recovery from COVID-19 illness since supplementation improves recovery from critical illness from COVID-19. ¹¹ Thiamine supplementation in the metabolic syndrome downregulates NF-κB. ¹² Thiamine is an essential cofactor for robust antibody responses as well. Subclinical deficiencies are commonplace in the setting of carbohydrate excess in today's Western diet. ¹³

Clinical trials involving all five micronutrients need to be funded and conducted in an appropriate manner even though there is little likelihood of substantial profit to their manufacturers, and thus such studies will need to be funded by government or foundation support. Proper amounts of these nutrients are likely necessary, if not sufficient, to correct clinical features of neurocovid. Western lifestyles and diets often lead to deficiencies of both vitamin D and magnesium as well as the other micronutrients discussed especially in the elderly with chronic illnesses but also in other population subsets.

In addition to the essential micronutrients discussed so far, other nutrients, especially flavonoids, may have a role in the recovery from neurocovid. One such flavonoid, fisetin, not only downregulates NF-κB, but also decreases other inflammatory processes including interleukin-6 as well as tumor necrosis factor. ¹⁴ Fisetin has been shown to have effectiveness at reducing neurocognitive deficits in experimental models of AD ¹⁵ and may have an application in neurocovid as well.

Although there may be other promising interventions to be evaluated in this regard, including these micronutrients in designing studies of neurocovid, therapeutics would be an improvement from the current practice often overlooking the importance of adequate micronutrient status.