A new perspective on side effects of NSAIDs and corticosteroids
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. 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, 5,6,7 or gastrointestinal issues linked to impaired mucosal protective signaling, potentially due to reduced EP4 capacity 8. Individuals with “EP3 up” 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.
1 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
2 Bryson, T. et al. The Deleterious Role of the Prostaglandin E 2 EP3 Receptor in Angiotensin II Hypertension. American Journal of Physiology-Heart and Circulatory Physiology 318 (2020). https://doi.org/10.1152/ajpheart.00538.2019
3 Gu, X. et al. Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9 (2016). https://doi.org/10.1161/CIRCHEARTFAILURE.116.003291
4 Maxwell, D. L. et al. Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction. Life Sciences 313, 121277 (2023). https://doi.org/https://doi.org/10.1016/j.lfs.2022.121277
5 Hassouneh, R. et al. PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes. Diabetologia 59, 1318-1328 (2016). https://doi.org/10.1007/s00125-016-3916-5
6 Leng, J. et al. E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation. Kidney International 103, 100-114 (2023). https://doi.org/https://doi.org/10.1016/j.kint.2022.08.019
7 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 140, 56 (2020). https://doi.org/https://doi.org/10.1016/j.yjmcc.2019.11.135
8 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 24, 2002-2011 (2018). https://doi.org/10.2174/1381612824666180629111227