Altered Prostanoids: A Link between COVID-19 Severity, Obesity, and Age
An available medication used in Japan for allergies could be an effective treatment for COVID-19 in the elderly and overweight.
Obesity is associated with a pro-inflammatory state. Aging is also associated with changes in the immune system. Could there be a common change in inflammatory mediators in both of these populations that contributes to the increased risk of developing severe COVID-19?
Dr. Ajay Gupta, MD, MBBS (Chief Scientific Officer of Rockwell Medical, Inc) thinks so. He thinks the connection is prostanoids, in particular prostaglandin D2 and thromboxane A2. Prostaglandin D2, in particular, increases with age and obesity, providing a potential molecular link between these two conditions and the risk of developing severe COVID-19.
Prostaglandin D2 has complex effects that vary depending on which cell is responding and the receptor that it activates. The effects of prostaglandin D2 mediated by activation of one of its receptors (DP2) can contribute to symptoms of severe COVID-19. Signaling through DP2, prostaglandin D2 can cause an impaired antiviral immune response called the interferon response and can suppress the activity of multiple immune cells. Together, these effects prevent the body from clearing the virus and virally infected cells. Thus, these immune-suppressing effects of DP2 signaling let the virus replicate and cause severe pneumonia in the lungs and potentially infect and damage other tissues. Additionally, prostaglandin D2 signaling through DP2 triggers bronchoconstriction that makes it harder to breathe.
Through its other receptor, prostaglandin D2 actually has effects that are beneficial in COVID-19 patients. These include inhibition of the release of histamine by mast cells (reduces inflammation), inhibition of platelet aggregation (reduces blood clotting), and relaxation of smooth muscle and reduction in the permeability of blood vessels (make it easier to breathe).
Thus, the key to targeting prostaglandin D2 for treating COVID-19 is not to block its synthesis but to specifically block its stimulation of the receptor DP2, leaving DP1 activation intact.
Excessive blood clotting is a major complication of severe COVID-19. The primary function of thromboxane A2 is to promote blood clotting through its action on its receptor TP. Preventing the activity of thromboxane A2 at its receptor is expected to be beneficial in COVID-19 patients by preventing the complications and tissue damage arising from the excessive formation of blood clots.
Ramatroban is a medication that has been used in Japan to treat allergic rhinitis (nasal congestion and sneezing) since 2000. Ramatroban has two key targets both of which are relevant for COVID-19. Ramatroban inhibits the prostaglandin D2 receptor DP2 and the thromboxane A2 receptor TP. Thus, ramatroban represents a potentially dual-acting therapy that can both promote immune-mediated clearance of the virus and prevent the formation of dangerous blood clots.
Dr. Gupta is so confident that ramatroban will be useful in treating COVID-19 he has 3 provisional patent applications (63/003,286; 63/005,205; 63/027,751) for the use of ramatroban in COVID-19. He is also trying to get ramatroban included in clinical trials for COVID-19.
Note: This article was corrected on 11 December 2020. The term prostacyclins was incorrect and has been corrected to prostanoids.
References related to ramatroban and prostaglandin D2
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Gupta A, Kalantar-Zadeh K, Reddy ST. Ramatroban as a Novel Immunotherapy for COVID-19. J. Mol. Genet. Med. 14:10.37421/jmgm.2020.14.457 (2020). DOI:10.37421/jmgm.2020.14.457
Gupta A, Chiang KC, Prostaglandin D2 as a mediator of lymphopenia and a therapeutic target in COVID-19 disease. Medical Hypotheses 143: 110122 (2020) DOI: 10.1016/j.mehy.2020.110122
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