Since the beginning of the Covid-19 pandemic, corticosteroids, also known as GCs (glucocorticoids), have established themselves as one of the main treatment options – especially in severe cases – due to their anti-inflammatory and immunosuppressive action. Now, Brazilian researchers have just discovered new mechanisms of action of these drugs in controlling the body’s inflammatory response during infection: they increase the levels of eCB (endocannabinoids), molecules produced by the body itself that bind to the same cannabidiol receptor, and decrease the plasma concentration of a lipid mediator known as PAF (platelet activating factor), which regulates clotting. The results of the study were published in the journal Viruses.
“Since endocannabinoids have neurological and anti-inflammatory functions, our idea was to investigate whether patients with mild symptoms of Covid-19 had greater protection thanks to the natural production of these molecules and whether in severe cases the levels were lower, causing exacerbated inflammation and, consequently, , ICU admissions [Unidade de Terapia Intensiva]”, explains Carlos Arterio Sorgi, professor at the Department of Chemistry at FFCLRP-USP (Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo) and coordinator of the work.
Another objective of the study, which was supported by FAPESP (projects 22/07287-2 and 21/04590-3), was to find out whether PAF was more present in the most serious manifestations of Covid-19, stimulating blood clotting and formation of microthrombi. For this analysis, the group used the infrastructure of CEQIL (Center of Excellence for Quantification and Identification of Lipids) at FCFRP-USP (Faculty of Pharmaceutical Sciences of Ribeirão Preto), acquired with support from the Foundation under the EMU (Multi-user Equipment) program. .
Using high-resolution mass spectrometry, however, the researchers observed the opposite of what was expected: critically ill patients had increased levels of endocannabinoids and reduced PAF in their blood plasma.
In order to understand these findings, it was necessary to analyze in detail each data from a large group of patients with mild and severe symptoms, being treated at home, in the ward or in the ICU, as well as all their clinical parameters and pharmacological management. Then, multivariate statistical tests were applied to this information.
“We understood, then, that it was not the disease that was responsible for increasing the endocannabinoids and decreasing the PAF, but rather the treatment with corticoids”, says Sorgi. “Although the classical pharmacology mechanism of this class of drugs was already widely known, their effects on these biomolecules had never been demonstrated in the literature.”
Analysis of the transcriptome of blood leukocytes (set of RNAs expressed by these defense cells) from patients treated with corticosteroids also showed differentiated gene expression of monoacylglycerol lipase and phospholipase A2, revealing that corticosteroids can alter the activity of enzymes involved in the metabolism of mediators analyzed lipids.
new treatments
The findings open up future possibilities for corticosteroid-based treatments not only for Covid-19 but for other serious inflammatory and neurological diseases. They also indicate that cannabinoids – natural or artificial – may possibly work as an adjunctive therapy. “Combining the effects of the two compounds would create the best possible scenario”, believes Sorgi.
The next rounds of studies should involve patients with other viral diseases, such as the flu, to analyze whether in these cases the production of such lipid biomolecules is also altered by the action of corticoids. In addition, it will be investigated whether the organism maintains the same endocannabinoid production capacity after vaccination against Covid-19 and during the convalescence of the disease.
“We are still interested in making associations with groups that work with cannabidiol for tests in experimental animal models, since we are now in a different phase of Covid-19”, says Sorgi.
The work is part of the ImunoCovid consortium, which involves, in addition to the Department of Chemistry at FFCLRP-USP, the departments of Clinical, Toxicological and Bromatological Analysis at FCFRP-USP (Faculty of Pharmaceutical Sciences of Ribeirão Preto), of Biochemistry and Immunology, of Surgery and Anatomy and Internal Medicine at FMRP-USP (Faculty of Medicine of Ribeirão Preto) and General and Specialized Nursing at EERP-USP (School of Nursing of Ribeirão Preto).
Scientists from the Department of Genetics and Evolution at CCBS-UFSCar (Center for Biological and Health Sciences at the Federal University of São Carlos), Hospital Santa Casa de Misericórdia de Ribeirão Preto and ICB-UFAM (Institute of Biological Sciences at the University Federal do Amazonas). The first authorship is shared by a FAPESP scientific initiation fellow, Jonatan Constança Silva de Carvalho, a doctoral student, Diana Mota Toro, and doctors Pedro Vieira da Silva-Neto, Carlos Alessandro Fuzo and Viviani Nardini, from USP in Ribeirão Preto .