Other potential stategies to modulate PGE2 and EP receptor activity
Hypothetical potential intervention: |
Hypothetical mechanisms of action: | |||
Pharmaceuticals that could rebalance EP receptor availability – not tested for Long COVID – |
||||
Pharmacological EP-antagonists/agonists |
Agonism or antagonism of specific EP receptors may represent a potential strategy to adjust imbalanced physiological EP receptor signaling in patients with long COVID |
|||
| EP1 ANTAGONISTS SC19220 1 ONO-AE829 2 AH6809 3 |
EP1 AGONISTS Iloprost1 17-phenyl-trinor-PGE(2) 3,4 |
EP2 ANTAGONISTS AH6809 5 PF-04418948 6 |
EP2 AGONISTS Butaprost1 ONO-AE1-259 7 |
|
| EP3 ANTAGONISTS 2-amino thiadiazole amiden 8 ONO-AE3-240 9 AE5-599 10 AE3-240 10 |
EP3 AGONISTS Sulprostone 11 ONO-AE3-208 9 BGC20-1531 12 ONO-AE-248 9,13,14 |
EP4 ANTAGONISTS Enprostil 15 ONO-NT012 16 |
EP4 AGONISTS ONO-AE1-329 17 and more full agonists 18 |
|
| Medication that reportedly decreases PGE2 acitvity – not tested for Long COVID – | ||||
PGE1- [34] and PGE3-analogs 19 |
These analogs can reduce the adverse influence of PGE2 by binding to the EP-receptors as rival ligands 19. may provide benefits across the four sub-phenotypes |
| 15-PGDH-activators 20 |
15-PGDH degrades PGE2 (and some other prostaglandins) into its inactive metabolite. Increasing 15-PGDH could help to decrease PGE2 activity more selectively than with NSAIDs 20. potentially safer combined with EP receptor agonism or inhibition |
mPGES-1 inhibitors Sulforaphane 21 – other mPGES-1inhibitors or suppressors 22-24 – Dual COX-LOX inhibitors 25 NSAIDs combined with EP receptor agonism or inhibition Example with EP4 antagonist ONO-AE3-208 26 |
These medications target steps in the synthesis or degradation of PGE2, possibly in combination with EP-receptor (ant)agonists, to decrease side effects potentially safer combined with EP receptor agonism or inhibition |
Metformin Review on LC interventions 27 “Early findings suggest that metformin has the strongest clinical evidence, particularly from large phase 3 trials” |
Metformin reduces PGE2 activity 28, 29,30 potentially beneficial “for EP3 up”potentially contra-indicated for “EP3 down” see section 2.1 below |
Pharmalogical agent that reportedly can increase EP3 expression – not tested for Long COVID – |
|
Demethylating DNA with 5-aza-dC to increase expression of EP3 receptors31 |
This compound has been shown to increase/restore the expression of EP3-receptors by demethylation 31 Contra-indicated for “EP3 up” |
| Psychopharmacological agents that elevate monoamine levels through shared subcellular signaling pathways monoamines may reduce PGE2 activity (but they could increase it aswell, depending on the dose and other factors). – tested for Long COVID, partially succesful – |
|
Methylphenidate Two LC case series 32,33 |
Methylphenidate increases DA levels 34 |
| Bupropion LC case series 35 | Bupropion is a DA and noradrenalin reuptake inhibitor, increasing their levels 35. |
SSRI’s 36,37 “After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors” 61 |
SSRI’s raise serotonin levels “This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response” |
– not tested for long COVID – |
|
Melatonin We found no melatonin trial for long COVID “On the protective effect of melatonin in severe-COVID-19 patients. The protocol consisted of standard therapy with oxygen intubation, remdesivir, levofloxacin, dexamethasone, and enoxaparin. Half of the patients additionally received 10 mg of melatonin. Interestingly, the mortality rate was 17.1% in the conventional therapy group and 1.2% in melatonin group; thus, overall, the mortality was reduced by 93% in patients treated with melatonin”. 38 |
Melatonin is reported to decrease PGE2 activity by modulating cAMP 39,40 potentially more beneficial “for EP3 up”potentially contra-indicated for “EP3 down” see section 2.2 below on modulating cAMP |
Immunoadsorption Preliminary studies on the treatment of ME/CFS patients 41 “Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement” |
Removes IgG type autoantibodies Review article “Chronic inflammation in Long COVID relationship to autoimmune diseases” 42 “We intervene in the treatment of the disease with probiotics, immunoglobulins, the RECOVER clinical trial model, and immunomodulatory drugs. The aim is to enhance understanding of the pathophysiological mechanism of Long COVID and to provide a reference for the immunotherapy of patients.” potentially beneficial for patients with EP2 up and/or EP4 up (“EP3 down”) |
1 Botella, A., Delvaux, M., Fioramonti, J., Frexinos, J. & Bueno, L. Stimulatory (EP1 and EP3) and inhibitory (EP2) prostaglandin E2 receptors in isolated ileal smooth muscle cells. Eur J Pharmacol 237, 131-137 (1993). https://doi.org/10.1016/0014-2999(93)90102-n
2 Takeuchi, K., Araki, H., Umeda, M., Komoike, Y. & Suzuki, K. Adaptive gastric cytoprotection is mediated by prostaglandin EP1 receptors: a study using rats and knockout mice. J Pharmacol Exp Ther 297, 1160-1165 (2001).
3 Rutkai, I. et al. Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes. Cardiovasc Res 83, 148-154 (2009). https://doi.org/10.1093/cvr/cvp098
4 Araki, H. et al. The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Aliment Pharmacol Ther 14 Suppl 1, 116-124 (2000). https://doi.org/10.1046/j.1365-2036.2000.014s1116.x
5 Li, P. et al. AH6809 decreases production of inflammatory mediators by PGE(2) – EP2 – cAMP signaling pathway in an experimentally induced pure cerebral concussion in rats. Brain Res 1698, 11-28 (2018). https://doi.org/10.1016/j.brainres.2018.05.030
6 Säfholm, J. et al. Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor. J Allergy Clin Immunol 136, 1232-1239.e1231 (2015). https://doi.org/10.1016/j.jaci.2015.04.002
7 Ota, H. et al. EP2 receptor plays pivotal roles in generating mechanical hyperalgesia after lengthening contractions. Scand J Med Sci Sports 28, 826-833 (2018). https://doi.org/10.1111/sms.12954
8 Hilfiker, M. et al. Discovery of novel aminothiadiazole amides as selective EP3 receptor antagonists. Bioorganic & medicinal chemistry letters 19, 4292-4295 (2009). https://doi.org/10.1016/j.bmcl.2009.05.074
9 Nagano, T. et al. Prostaglandin E(2) increases the expression of cyclooxygenase-2 in cultured rat microglia. J Neuroimmunol 361, 577724 (2021). https://doi.org/10.1016/j.jneuroim.2021.577724
10 Schober, L. J. et al. The role of PGE2 in human atherosclerotic plaque on platelet EP3 and EP4 receptor activation and platelet function in whole blood. Journal of Thrombosis and Thrombolysis 32, 158-166 (2011). https://doi.org/10.1007/s11239-011-0577-6
11 Nazabal, A., Mendiguren, A. & Pineda, J. Inhibition of rat locus coeruleus neurons by prostaglandin E2 EP3 receptors: pharmacological characterization ex vivo. Frontiers in Pharmacology 14 (2023). https://doi.org/10.3389/fphar.2023.1290605
12 Antonova, M. et al. The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache. J Headache Pain 12, 551-559 (2011). https://doi.org/10.1007/s10194-011-0358-9
13 Mori, A. et al. Effects of specific prostanoid EP receptor agonists on cell proliferation and intracellular Ca(2+) concentrations in human airway smooth muscle cells. Eur J Pharmacol 659, 72-78 (2011). https://doi.org/10.1016/j.ejphar.2011.03.001
14 Minami, T. et al. Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice. Br J Pharmacol 133, 438-444 (2001). https://doi.org/10.1038/sj.bjp.0704092
15 Takeuchi, K., Yagi, K., Kato, S. & Ukawa, H. Roles of prostaglandin E-receptor subtypes in gastric and duodenal bicarbonate secretion in rats. Gastroenterology 113, 1553-1559 (1997). https://doi.org/10.1053/gast.1997.v113.pm9352857
16 Hase, S., Yokota, A., Nakagiri, A. & Takeuchi, K. Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors. Life Sciences 74, 629-641 (2003). https://doi.org/https://doi.org/10.1016/j.lfs.2003.07.010
17 Ariumi, H. et al. Roles of the central prostaglandin EP3 receptors in cardiovascular regulation in rats. Neurosci Lett 324, 61-64 (2002). https://doi.org/10.1016/s0304-3940(02)00174-x
18 Wilson, R. J. et al. Functional pharmacology of human prostanoid EP2 and EP4 receptors. Eur J Pharmacol 501, 49-58 (2004). https://doi.org/10.1016/j.ejphar.2004.08.025
19 Robertson, R. P. The COX-2/PGE(2)/EP3/G(i/o)/cAMP/GSIS Pathway in the Islet: The Beat Goes On. Diabetes 66, 1464-1466 (2017). https://doi.org/10.2337/dbi17-0017
20 Sun, C. C. et al. Recent advances in studies of 15-PGDH as a key enzyme for the degradation of prostaglandins. Int Immunopharmacol 101, 108176 (2021). https://doi.org/10.1016/j.intimp.2021.108176
21 Zhou, J., Joplin, D. G., Cross, J. V. & Templeton, D. J. Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1. PLOS ONE 7, e49744 (2012). https://doi.org/10.1371/journal.pone.0049744
22 Park, J. Y., Pillinger, M. H. & Abramson, S. B. Prostaglandin E2 synthesis and secretion: The role of PGE2 synthases. Clinical Immunology 119, 229-240 (2006). https://doi.org/https://doi.org/10.1016/j.clim.2006.01.016
23 Khan, H. et al. Plant-derived mPGES-1 inhibitors or suppressors: A new emerging trend in the search for small molecules to combat inflammation. European Journal of Medicinal Chemistry 153, 2-28 (2018). https://doi.org/https://doi.org/10.1016/j.ejmech.2017.12.059
24 Ikeda-Matsuo, Y. et al. Microsomal prostaglandin E synthase-1 is a critical factor in dopaminergic neurodegeneration in Parkinson’s disease. Neurobiology of Disease 124, 81-92 (2019). https://doi.org/https://doi.org/10.1016/j.nbd.2018.11.004
25 Mukhopadhyay, N., Shukla, A., Makhal, P. N. & Kaki, V. R. Natural product-driven dual COX-LOX inhibitors: Overview of recent studies on the development of novel anti-inflammatory agents. Heliyon 9, e14569 (2023). https://doi.org/10.1016/j.heliyon.2023.e14569
26 Pavlovic, S. et al. Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages. J Biol Chem 281, 3321-3328 (2006). https://doi.org/10.1074/jbc.M506846200
27 Livieratos, A., Gogos, C. & Akinosoglou, K. Beyond Antivirals: Alternative Therapies for Long COVID. Viruses 16 (2024). https://doi.org/10.3390/v16111795
28 Han, Y. et al. Metformin decreases LPS-induced inflammatory response in rabbit annulus fibrosus stem/progenitor cells by blocking HMGB1 release. Aging (Albany NY) 11, 10252-10265 (2019). https://doi.org/10.18632/aging.102453
29 Zhou, Y. et al. Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells. Reprod Sci 22, 1162-1170 (2015). https://doi.org/10.1177/1933719115590664
30 Kalariya, N. M., Shoeb, M., Ansari, N. H., Srivastava, S. K. & Ramana, K. V. Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 53, 3431-3440 (2012). https://doi.org/10.1167/iovs.12-9432
31 Fukushima, K. & Fujino, H. Identification and Characterization of Human Colorectal Cancer Cluster Predominantly Expressing EP3 Prostanoid Receptor Subtype. Biological and Pharmaceutical Bulletin 45, 698-702 (2022). https://doi.org/10.1248/bpb.b22-00104
32 Clark, P. et al. Methylphenidate for the Treatment of Post-COVID Cognitive Dysfunction (Brain Fog). J Med Cases 15, 195-200 (2024). https://doi.org/10.14740/jmc4254
33 Morelli-Zaher, C. et al. Post-COVID central hypersomnia, a treatable trait in long COVID: 4 case reports. Front Neurol 15, 1349486 (2024). https://doi.org/10.3389/fneur.2024.1349486
34 Gottlieb, S. Methylphenidate works by increasing dopamine levels. Bmj 322, 259 (2001). https://doi.org/10.1136/bmj.322.7281.259
35 Reinfeld, S. Can bupropion treat COVID-19–induced brain fog? A case series. International Clinical Psychopharmacology 38, 189-191 (2023). https://doi.org/10.1097/yic.0000000000000436
36 Rus, C. P., de Vries, B. E. K., de Vries, I. E. J., Nutma, I. & Kooij, J. J. S. Treatment of 95 post-Covid patients with SSRIs. Scientific Reports 13, 18599 (2023). https://doi.org/10.1038/s41598-023-45072-9
37 Seo, Y. B. et al. Therapeutic options for the treatment of post-acute sequelae of COVID-19: a scoping review. BMC Infect Dis 25, 731 (2025). https://doi.org/10.1186/s12879-025-11131-x
38 Catalano, A. et al. Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment? Foods 11 (2022). https://doi.org/10.3390/foods11182884
39 Carrillo-Vico, A., García-Mauriño, S., Calvo, J. R. & Guerrero, J. M. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. The FASEB Journal 17, 755-757 (2003). https://doi.org/https://doi.org/10.1096/fj.02-0501fje
40 Tse, L. H., Cheung, S. T., Lee, S. & Wong, Y. H. Real-Time Determination of Intracellular cAMP Reveals Functional Coupling of G(s) Protein to the Melatonin MT(1) Receptor. Int J Mol Sci 25 (2024). https://doi.org/10.3390/ijms25052919
41 Preßler, H. et al. IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS). Trials 25, 172 (2024). https://doi.org/10.1186/s13063-024-07982-5
42 Chen, K. et al. Chronic inflammation in Long COVID relationship to autoimmune diseases. Autoimmun Rev 24, 103882 (2025). https://doi.org/10.1016/j.autrev.2025.103882