{"id":2027,"date":"2026-04-12T22:35:43","date_gmt":"2026-04-12T22:35:43","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=2027"},"modified":"2026-09-02T05:08:02","modified_gmt":"2026-09-02T05:08:02","slug":"perspectieven-van-een-gevalideerde-hypothese","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=2027","title":{"rendered":"Perspectieven van een gevalideerde hypothese"},"content":{"rendered":"\t\t
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Other potential stategies to modulate PGE2 and EP receptor activity<\/strong><\/h3>\n\n
\n\n\n\n\n\n\n\n\n\n

<\/strong>Hypothetical potential intervention:

<\/strong><\/td>\n		Hypothetical mechanisms of action:<\/strong><\/td>\n<\/tr>\n

Pharmaceuticals that could rebalance EP receptor availability – not tested for Long COVID –<\/td>\n<\/tr>\n

Pharmacological<\/strong>
EP-antagonists\/agonists<\/strong><\/td>\n
<\/em>Agonism or antagonism of specific EP receptors may represent a potential strategy to adjust imbalanced physiological EP receptor signaling in patients with long COVID<\/td>\n<\/tr>\n
EP1<\/strong> ANTAGONISTS SC19220 1<\/sup>
ONO-AE829 2<\/sup>
AH6809 3<\/sup><\/td>\n		\u00a0EP1<\/strong> AGONISTS \u00a0Iloprost1<\/sup>
\u00a017-phenyl-trinor-PGE(2) 3,4<\/sup><\/td>\n		\u00a0EP2 <\/strong>ANTAGONISTS \u00a0AH6809 5<\/sup>
\u00a0PF-04418948 6<\/sup><\/td>\n		\u00a0EP2 <\/strong>AGONISTS \u00a0Butaprost1<\/sup>
\u00a0ONO-AE1-259 7<\/sup><\/td>\n<\/tr>\n
EP3<\/strong> ANTAGONISTS \u00a02-amino thiadiazole amiden 8<\/sup>
ONO-AE3-240 9<\/sup>\u00a0
AE5-599 10<\/sup>
AE3-240 10<\/sup><\/td>\n		\u00a0EP3<\/strong> AGONISTS \u00a0Sulprostone 11<\/sup>
ONO-AE3-208 9<\/sup>
\u00a0BGC20-1531 12<\/sup>
ONO-AE-248 9,13,14<\/sup><\/td>\n		\u00a0EP4<\/strong> ANTAGONISTS

Enprostil 15<\/sup>
\u00a0ONO-NT012 16<\/sup>
\u00a0<\/td>\n		\u00a0EP4<\/strong> AGONISTS ONO-AE1-329 17<\/sup>
\u00a0and more
\u00a0full agonists 18<\/sup><\/td>\n<\/tr>\n
\u00a0 Medication that reportedly decreases PGE2 acitvity – not tested for Long COVID –<\/td>\n<\/tr>\n
\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n\u00a0<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n\n
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n

PGE1- [34] and PGE3-analogs <\/strong>19<\/sup><\/td>\n
These analogs can reduce the adverse influence of PGE2 by binding to the EP-receptors as rival ligands 19<\/sup>. may provide benefits across the four sub-phenotypes<\/td>\n<\/tr>\n
\u00a0
<\/strong>15-PGDH-activators<\/strong> 20<\/sup><\/td>\n
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<\/sup>. potentially safer combined with EP receptor agonism or inhibition<\/td>\n<\/tr>\n

mPGES-1 inhibitors<\/strong>
Sulforaphane 21<\/sup>
– other mPGES-1inhibitors or suppressors 22-24<\/sup>
– Dual COX-LOX inhibitors 25<\/sup>
NSAIDs combined with EP receptor agonism or inhibition<\/strong> Example with EP4 antagonist ONO-AE3-208 26<\/sup><\/td>\n
<\/em>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<\/td>\n<\/tr>\n

Metformin<\/strong> Review on LC interventions 27<\/sup> \u201cEarly findings suggest that metformin has the strongest clinical evidence, particularly from large phase 3 trials\u201d<\/td>\n
Metformin reduces PGE2 activity 28<\/sup>, <\/sup>29<\/sup>,<\/sup>30<\/sup> potentially beneficial \u201cfor EP3 up\u201dpotentially contra-indicated for \u201cEP3 down\u201d see section 2.1 below \u00a0<\/td>\n<\/tr>\n

Pharmalogical agent that reportedly can increase EP3 expression – not tested for Long COVID –<\/td>\n<\/tr>\n

Demethylating DNA with 5-aza-dC<\/strong> to increase expression of EP3 receptors31<\/sup><\/td>\n
<\/em>This compound has been shown to increase\/restore the expression of EP3-receptors by demethylation 31<\/sup> Contra-indicated for \u201cEP3 up\u201d<\/td>\n<\/tr>\n
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 –<\/td>\n<\/tr>\n

Methylphenidate

<\/strong> Two LC case series 32,33<\/sup><\/td>\n
Methylphenidate increases DA levels 34<\/sup>



<\/td>\n<\/tr>\n
Bupropion<\/strong> \u00a0 LC case series 35<\/sup><\/td>\n\u00a0 Bupropion is a DA and noradrenalin reuptake inhibitor, increasing their levels 35<\/sup>. \u00a0 \u00a0<\/td>\n<\/tr>\n

SSRI\u2019s <\/strong>36,37<\/sup>

\u201cAfter a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors\u201d 61<\/sup><\/a>

<\/td>\n
SSRI\u2019s raise serotonin levels

\u201cThis study used an exploratory questionnaire and found that two-thirds<\/em> of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response\u201d \u00a0<\/td>\n<\/tr>\n

– not tested for long COVID –<\/td>\n<\/tr>\n

Melatonin<\/strong> We found no melatonin trial for long COVID \u201cOn the protective effect of melatonin in severe-COVID-19<\/em> 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\u201d. 38<\/sup>

<\/td>\n
Melatonin is reported to decrease PGE2 activity by modulating cAMP 39,40<\/sup>

potentially more beneficial \u201cfor EP3 up\u201dpotentially contra-indicated for \u201cEP3 down\u201d see section 2.2 below on modulating cAMP \u00a0<\/td>\n<\/tr>\n

Immunoadsorption<\/strong> \u00a0<\/strong> Preliminary studies on the treatment of ME\/CFS patients 41<\/sup> \u00a0<\/strong> \u201cPreliminary studies on the treatment of ME\/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement\u201d \u00a0<\/td>\n
Removes IgG type autoantibodies Review article \u201cChronic inflammation in Long COVID relationship to autoimmune diseases\u201d 42<\/sup> \u201cWe 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.\u201d potentially beneficial for patients with EP2 up and\/or EP4 up (\u201cEP3 down\u201d)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/figure>\n\n

1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 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<\/em> 237<\/strong>, 131-137 (1993). https:\/\/doi.org\/10.1016\/0014-2999(93)90102-n<\/a><\/p>\n\n

2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 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<\/em> 297<\/strong>, 1160-1165 (2001).<\/p>\n\n

3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Rutkai, I. et al.<\/em> Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes. Cardiovasc Res<\/em> 83<\/strong>, 148-154 (2009). https:\/\/doi.org\/10.1093\/cvr\/cvp098<\/a><\/p>\n\n

4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Araki, H. et al.<\/em> The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Aliment Pharmacol Ther<\/em> 14 Suppl 1<\/strong>, 116-124 (2000). https:\/\/doi.org\/10.1046\/j.1365-2036.2000.014s1116.x<\/a><\/p>\n\n

5\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Li, P. et al.<\/em> AH6809 decreases production of inflammatory mediators by PGE(2) – EP2 – cAMP signaling pathway in an experimentally induced pure cerebral concussion in rats. Brain Res<\/em> 1698<\/strong>, 11-28 (2018). https:\/\/doi.org\/10.1016\/j.brainres.2018.05.030<\/a><\/p>\n\n

6\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 S\u00e4fholm, J. et al.<\/em> Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor. J Allergy Clin Immunol<\/em> 136<\/strong>, 1232-1239.e1231 (2015). https:\/\/doi.org\/10.1016\/j.jaci.2015.04.002<\/a><\/p>\n\n

7\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ota, H. et al.<\/em> EP2 receptor plays pivotal roles in generating mechanical hyperalgesia after lengthening contractions. Scand J Med Sci Sports<\/em> 28<\/strong>, 826-833 (2018). https:\/\/doi.org\/10.1111\/sms.12954<\/a><\/p>\n\n

8\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Hilfiker, M. et al.<\/em> Discovery of novel aminothiadiazole amides as selective EP3 receptor antagonists. Bioorganic & medicinal chemistry letters<\/em> 19<\/strong>, 4292-4295 (2009). https:\/\/doi.org\/10.1016\/j.bmcl.2009.05.074<\/a><\/p>\n\n

9\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Nagano, T. et al.<\/em> Prostaglandin E(2) increases the expression of cyclooxygenase-2 in cultured rat microglia. J Neuroimmunol<\/em> 361<\/strong>, 577724 (2021). https:\/\/doi.org\/10.1016\/j.jneuroim.2021.577724<\/a><\/p>\n\n

10\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Schober, L. J. et al.<\/em> 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<\/em> 32<\/strong>, 158-166 (2011). https:\/\/doi.org\/10.1007\/s11239-011-0577-6<\/a><\/p>\n\n

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12\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Antonova, M. et al.<\/em> The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache. J Headache Pain<\/em> 12<\/strong>, 551-559 (2011). https:\/\/doi.org\/10.1007\/s10194-011-0358-9<\/a><\/p>\n\n

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16\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Hase, S., Yokota, A., Nakagiri, A. & Takeuchi, K. Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors. Life Sciences<\/em> 74<\/strong>, 629-641 (2003). https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.lfs.2003.07.010<\/a><\/p>\n\n

17\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ariumi, H. et al.<\/em> Roles of the central prostaglandin EP3 receptors in cardiovascular regulation in rats. Neurosci Lett<\/em> 324<\/strong>, 61-64 (2002). https:\/\/doi.org\/10.1016\/s0304-3940(02)00174-x<\/a><\/p>\n\n

18\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Wilson, R. J. et al.<\/em> Functional pharmacology of human prostanoid EP2 and EP4 receptors. Eur J Pharmacol<\/em> 501<\/strong>, 49-58 (2004). https:\/\/doi.org\/10.1016\/j.ejphar.2004.08.025<\/a><\/p>\n\n

19\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Robertson, R. P. The COX-2\/PGE(2)\/EP3\/G(i\/o)\/cAMP\/GSIS Pathway in the Islet: The Beat Goes On. Diabetes<\/em> 66<\/strong>, 1464-1466 (2017). https:\/\/doi.org\/10.2337\/dbi17-0017<\/a><\/p>\n\n

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36\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 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<\/em> 13<\/strong>, 18599 (2023). https:\/\/doi.org\/10.1038\/s41598-023-45072-9<\/a><\/p>\n\n

37\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Seo, Y. B. et al.<\/em> Therapeutic options for the treatment of post-acute sequelae of COVID-19: a scoping review. BMC Infect Dis<\/em> 25<\/strong>, 731 (2025). https:\/\/doi.org\/10.1186\/s12879-025-11131-x<\/a><\/p>\n\n

38\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Catalano, A. et al.<\/em> Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment? Foods<\/em> 11<\/strong> (2022). https:\/\/doi.org\/10.3390\/foods11182884<\/a><\/p>\n\n

39\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Carrillo-Vico, A., Garc\u00eda-Mauri\u00f1o, 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<\/em> 17<\/strong>, 755-757 (2003). https:\/\/doi.org\/https:\/\/doi.org\/10.1096\/fj.02-0501fje<\/a><\/p>\n\n

40\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 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<\/em> 25<\/strong> (2024). https:\/\/doi.org\/10.3390\/ijms25052919<\/a><\/p>\n\n

41\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Pre\u00dfler, H. et al.<\/em> 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<\/em> 25<\/strong>, 172 (2024). https:\/\/doi.org\/10.1186\/s13063-024-07982-5<\/a><\/p>\n\n

42\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Chen, K. et al.<\/em> Chronic inflammation in Long COVID relationship to autoimmune diseases. Autoimmun Rev<\/em> 24<\/strong>, 103882 (2025). https:\/\/doi.org\/10.1016\/j.autrev.2025.103882<\/a><\/p>\n\n

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