Anti-inflammatory Therapy by Cholinergic and Purinergic Modulation in Multiple Sclerosis Associated with SARS-CoV-2 Infection

Abstract

The virus "acute respiratory syndrome coronavirus 2" (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 , initially responsible for an outbreak of pneumonia in Wuhan, China, which, due to the high level of contagion and dissemination, has become a pandemic. The clinical picture varies from mild to critical cases; however, all of these signs already show neurological problems, from sensory loss to neurological diseases. Thus, patients with multiple sclerosis (MS) infected with the new coronavirus are more likely to develop severe conditions; in addition to worsening the disease, this is due to the high level of pro-inflammatory cytokines, which is closely associated with increased mortality both in COVID-19 and MS. This increase is uncontrolled and exaggerated, characterizing the cytokine storm, so a possible therapy for this neuronal inflammation is the modulation of the cholinergic anti-inflammatory pathway, since acetylcholine (ACh) acts to reduce pro-inflammatory cytokines and acts directly on the brain for being released by cholinergic neurons, as well as acting on other cells such as immune and blood cells. In addition, due to tissue damage, there is an exacerbated release of adenosine triphosphate (ATP), potentiating the inflammatory process and activating purinergic receptors which act directly on neuroinflammation and positively modulate the inflammatory cycle. Associated with this, in neurological pathologies, there is greater expression of P2X7 in the cells of the microglia, which positively activates the immune inflammatory response. Thus, the administration of blockers of this receptor can act in conjunction with the action of ACh in the anticholinergic inflammatory pathway. Finally, there will be a reduction in the cytokine storm and triggered hyperinflammation, as well as the level of mortality in patients with multiple sclerosis infected with SARS-CoV-2 and the development of possible neurological damage.

Alterations in CD39/CD73 axis of T cells associated with COVID‐19 severity

“…Interestingly, a pilot clinical trial demonstrated that elderly COVID-19 patients taking between 1.2 and 1.6 g of oral ATP daily had improved COVID-19 survival and fewer clinical symptoms compared to the control infected group (Abraham et al, 2021). Thus, the association between adenine-based purine molecules and clinical symptoms may indicate that purinergic signaling could be a target for pharmacologic therapies as previously suggested by hypotheses studies (Berger et al, 2022;Hasan et al, 2022;Simões et al, 2021). Also, the correlation analysis revealed a positive correlation between extracellular ATP levels and the peripheral frequency of low differentiated CD8 + T cells.…”

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…There is growing appreciation that targeting purinergic receptors may bring benefit to treat SARS-CoV-2 induced processes associated with the pathologies of COVID-19 (216)(217)(218)(219)(220)(221)(222). Accumulated clues to the puzzle of SARS-CoV-2 have suggested that when a virus can initiate platelet and neutrophil driven exacerbated macrophage inflammatory circuits, this can spell a pandemic.…”

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best

“…In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis might explain the systemic impaired microcirculatory function in different vascular beds and their clinical squeal in patients with COVID-19 (Simões et al 2021 ; Elekhnawy et al 2022 ). Vascular endothelins and consequent ED can be a principal determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure.…”