{"id":3376,"date":"2026-04-24T20:55:23","date_gmt":"2026-04-24T20:55:23","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=3376"},"modified":"2026-08-30T11:55:32","modified_gmt":"2026-08-30T11:55:32","slug":"side-effects-of-nsaids","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=3376","title":{"rendered":"Side effects of NSAIDs"},"content":{"rendered":"\t\t
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A new perspective on side effects of NSAIDs and corticosteroids<\/h2>\t\t\t\t<\/div>\n\t\t\t\t
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NSAIDs and corticosteroids are known to inhibit COX-2 and PGE2 production. However, these drugs are not always beneficial. Two non-exclusive explanations may account for these observations. First, NSAIDs reduce not only PGE2 but also other COX-2-derived prostaglandins with important physiological roles, including PGI2 (vasodilatation, anticoagulation) and TXA2 (vasoconstriction, coagulation)1<\/sup>. Second, lowering PGE2 levels does not necessarily correct imbalances in EP receptor expression and may even exacerbate disparities in EP3 versus EP2\/EP4 signaling: COX-2\/PGE2 downregulation is expected to favor increased EP3 expression with concomitant reductions in EP1, EP2, and EP4 (see section 3.1). Consequently, NSAID-associated adverse effects may reflect altered contributions of multiple COX-2-derived ligands combined with shifts in EP receptor expression.
Consistent with this notion, well-known NSAID side effects are mediated by PGE2 through EP3, such as cardiovascular and renal problems 2-4<\/sup>, <\/sup>5<\/sup>,<\/sup>6,7<\/sup> or gastrointestinal issues linked to impaired mucosal protective signaling, potentially due to reduced EP4 capacity 8<\/sup>. Individuals with \u201cEP3 up\u201d may be more prone to NSAID side effects, while other EP receptor imbalances can also trigger adverse effects after COX-2\/PGE2 inhibition, due to overactive or insufficient activity of specific prostaglandins. Thus, it might be safer to use COX-2 inhibitors in combination with specific EP receptor antagonists and agonists to decrease averse PGE2 activity. Such options are being researched 1<\/sup>.<\/p>\n\n

1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Pavlovic, S. et al.<\/em> 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<\/em> 281<\/strong>, 3321-3328 (2006). https:\/\/doi.org\/10.1074\/jbc.M506846200<\/a><\/p>\n\n

2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bryson, T. et al.<\/em> The Deleterious Role of the Prostaglandin E 2 EP3 Receptor in Angiotensin II Hypertension. American Journal of Physiology-Heart and Circulatory Physiology<\/em> 318<\/strong> (2020). https:\/\/doi.org\/10.1152\/ajpheart.00538.2019<\/a><\/p>\n\n

3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Gu, X. et al.<\/em> Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail<\/em> 9<\/strong> (2016). https:\/\/doi.org\/10.1161\/CIRCHEARTFAILURE.116.003291<\/a><\/p>\n\n

4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Maxwell, D. L. et al.<\/em> Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction. Life Sciences<\/em> 313<\/strong>, 121277 (2023). https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.lfs.2022.121277<\/a><\/p>\n\n

5\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Hassouneh, R. et al.<\/em> PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes. Diabetologia<\/em> 59<\/strong>, 1318-1328 (2016). https:\/\/doi.org\/10.1007\/s00125-016-3916-5<\/a><\/p>\n\n

6\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Leng, J. et al.<\/em> E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation. Kidney International<\/em> 103<\/strong>, 100-114 (2023). https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.kint.2022.08.019<\/a><\/p>\n\n

7\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Jing, L., Wen, Z. & Bin, L. The role of E-type prostaglandin receptor EP3 in acute renal injury induced by ischemia-reperfusion. Journal of Molecular and Cellular Cardiology<\/em> 140<\/strong>, 56 (2020). https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.yjmcc.2019.11.135<\/a><\/p>\n\n

8\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Takeuchi, K. & Amagase, K. Roles of Cyclooxygenase, Prostaglandin E2 and EP Receptors in Mucosal Protection and Ulcer Healing in the Gastrointestinal Tract. Curr Pharm Des<\/em> 24<\/strong>, 2002-2011 (2018). https:\/\/doi.org\/10.2174\/1381612824666180629111227<\/a><\/p>\n\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"

A new perspective on side effects of NSAIDs and corticosteroids \u00a0 NSAIDs and corticosteroids are known to inhibit COX-2 and […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"class_list":["post-3376","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/3376","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3376"}],"version-history":[{"count":16,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/3376\/revisions"}],"predecessor-version":[{"id":6423,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/3376\/revisions\/6423"}],"wp:attachment":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3376"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}