Newswise — Since the onset of the COVID-19 outbreak, a group of corticosteroids known as glucocorticoids (GCs) have emerged as a prominent treatment choice, particularly for critical cases, due to their anti-inflammatory and immunosuppressive effects. Recent findings from Brazilian scientists have unveiled fresh mechanisms through which these medications impact the body's inflammatory response during an infection: they elevate levels of endocannabinoids (eCBs), internally-produced molecules that bind to the same receptor as cannabidiol, while simultaneously reducing circulating levels of platelet-activating factor (PAF), an inflammatory and clotting mediator.
"Given the neurological and anti-inflammatory roles of endocannabinoids, our aim was to explore whether individuals experiencing mild symptoms of COVID-19 were afforded greater protection due to the natural production of these molecules, and whether their levels were diminished in severe cases, leading to heightened inflammation and a necessity for intensive care," stated Carlos Arterio Sorgi, the study's principal investigator and final author. Sorgi, a professor in the Department of Chemistry at the University of São Paulo's Ribeirão Preto School of Philosophy, Sciences and Letters (FFCLRP-USP) in São Paulo state, further added this information.
An additional objective of the study, which received support from FAPESP through projects 22/07287-2 and 21/04590-3, was to investigate whether elevated levels of PAF were present in severe cases of COVID-19. If confirmed, this could potentially elucidate the excessive formation of blood clots and microthrombi observed in these patients. To conduct this analysis, the research team utilized the resources provided by the Center of Excellence in Lipid Quantification and Identification (CEQIL), affiliated with the Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP). The necessary equipment for this investigation was acquired through funding obtained from FAPESP's Multiuser Equipment Program.
Employing high-resolution mass spectrometry, the researchers made a surprising observation contrary to their initial expectations: severe patients exhibited elevated levels of endocannabinoids and decreased levels of PAF.
To comprehend these findings, the researchers conducted a comprehensive analysis of data gathered from a substantial cohort of individuals, encompassing both mild and severe cases, who received treatment either at home, in hospital wards, or in intensive care units (ICUs). The analysis encompassed a range of clinical parameters and pharmaceutical interventions. Subsequently, the collected data underwent rigorous multivariate statistical tests.
"We have deduced that the elevation of endocannabinoids and reduction of PAF were not inherent to the disease itself, but rather a consequence of glucocorticoid (GCs) treatment," Sorgi explained. "While the conventional pharmacological actions of these drugs are well-established, their impact on these biomolecules had not been previously addressed in the scientific literature."
The examination of the transcriptome, encompassing all messenger RNA molecules, within leukocytes from patients treated with GCs, provided further insights. It revealed distinct modulation of gene expression related to monoacylglycerol lipase and phospholipase A2, highlighting the ability of these drugs to modify the activity of enzymes involved in the metabolism of the analyzed lipid mediators. Leukocytes, which are white blood cells constituting a crucial component of the immune system, were the focus of this investigation.
Novel treatments
The discoveries made in this study hold promising prospects for future treatments utilizing corticosteroids, not limited to COVID-19 but also extending to other severe inflammatory and neurological conditions. Additionally, the findings indicate the potential use of cannabinoids, whether naturally occurring or synthetic, as adjuvant therapy in these cases. These insights pave the way for exploring new therapeutic avenues and expanding the understanding of the therapeutic potential of corticosteroids and cannabinoids in various medical conditions.
“Combining the effects of the two compounds would create the best scenario possible,” Sorgi said.
The upcoming investigations will encompass studies involving patients afflicted with other viral diseases, such as influenza, to ascertain whether corticosteroid treatment similarly affects the production of the specific lipidic biomolecules. Additionally, researchers will explore whether the organism retains the same capability to generate endocannabinoids following COVID-19 vaccination and during the recovery period from the disease. These future studies aim to broaden our understanding of the broader implications of corticosteroid action and the potential impact on endocannabinoid production in various viral infections and post-vaccination scenarios.
Sorgi expressed the team's interest in collaborating with research groups conducting animal trials involving cannabidiol, as they have entered a distinct phase of COVID-19 investigation.
The researchers are part of the ImmunoCovid consortium, which encompasses various departments and institutions. This consortium includes the Chemistry Department at FFCLRP-USP, the Department of Clinical, Toxicological and Bromatological Analysis at FCFRP-USP, the Departments of Biochemistry and Immunology, Surgery and Anatomy, and Clinical Medicine at the Ribeirão Preto Medical School (FMRP-USP), and the Department of General and Specialist Nursing at the Ribeirão Preto Nursing School (EERP-USP). These collaborative efforts involve experts from multiple disciplines and institutions, fostering a comprehensive approach to the study of COVID-19.
The article's primary authors include Jonatan Constança Silva de Carvalho, who conducted the research with a scientific initiation scholarship from FAPESP. Additionally, Diana Mota Toro, a PhD candidate, Pedro Vieira da Silva-Neto, Viviani Nardini from FCFRP-USP, and Carlos Alessandro Fuzo, a researcher at FFCLRP-USP, also contributed significantly to the study. Their collective efforts and expertise played a crucial role in the development and findings of the research article.
In addition to the aforementioned authors, there are co-authors affiliated with various institutions. These include the Department of Genetics and Evolution at the Federal University of São Carlos's Center for Biological and Health Sciences (CCBS-UFSCar) in São Paulo state, the Santa Casa de Misericórdia Hospital in Ribeirão Preto, and the Institute of Biological Sciences (ICB-UFAM) at the Federal University of Amazonas. The collaboration of researchers from these institutions contributes to a broader range of expertise and diverse perspectives in the study.
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.
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