A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19

Abstract

The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.

Reactive Sulfur Compounds in the Fight against COVID-19

“…The best outcome was observed when LA and PEA were administered after LPS, thus reinforcing the hypothesis that LA combined with PEA is able to modulate the key point of cytokine storm syndrome. In the authors’ opinion, these results for the first time provide support to the conclusion that the combination of LA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and by acting as a powerful antioxidant [ 135 ].…”

“…Using the model of LPS-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome, it was shown that a combination of 50 µM LA and 5 µM palmitoylethanolamide (PEA) could reduce ROS and NO levels modulating the major cytokines involved in COVID-19 infection [ 135 ]. The best outcome was observed when LA and PEA were administered after LPS, thus reinforcing the hypothesis that LA combined with PEA is able to modulate the key point of cytokine storm syndrome.…”

Antioxidant and Anti-Inflammatory Activity of Combined Phycocyanin and Palmitoylethanolamide in Human Lung and Prostate Epithelial Cells

“…While PC is a known scavenger of ROS, a similar scavenging mechanism was not described for PEA. A previous study found that PEA downregulated the expression of TLR4, suggesting that the antioxidant effect of PEA was mediated by TLR4-dependent PPARα activation [ 51 ]. In our study we demonstrated an additional novel mechanism of PEA, the direct inhibition of COX-2, which can explain its antioxidant properties in addition to PPARα activation.…”

How to Restore Oxidative Balance That Was Disrupted by SARS-CoV-2 Infection

“…An in vitro study by Uberti, F., et al, evaluated the effect of ALA combined with palmitoylethanolamide (PEA) on lung cells under conditions of a stimulated cytokine storm. The authors demonstrated that an ALA and PEA combination could decrease ROS production [ 45 ]. Horowitz RI et al reported that application of glutathione, NAC and ALA in the treatment of COVID-19-related pneumonia in two patients resulted in an improvement in clinical courses and the alleviation of dyspnea [ 46 ].…”