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Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury

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Abstract

Introduction

Ischemia–reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality.

Materials and methods

A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury.

Conclusion

This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.

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Abbreviations

COX:

Cyclooxygenase

AA:

Arachidonic acid

PG:

Prostaglandin

TXA:

Thromboxanes

PES:

Prostaglandin endoperoxide synthase

TNF-α:

Tumour necrosis factor

IL-1β:

Interleukin

LPS:

Lipopolysaccharide

ALT:

Serum alanine aminotransferase

AST:

Aspartate aminotransferase

LDH:

Lactate dehydrogenase

NGAL:

Serum neutrophil gelatinase-associated lipocalin

PAF:

Platelet activating factor

PMNs:

Polymorphonuclear leucocytes

rt-PA:

Recombinant tissue plasminogen activator

iNOS:

Inducible nitric oxide synthase

BCAO:

Bilateral common carotid artery occlusion

References

  1. Khan H, Kashyap A, Kaur A, Singh TG. Pharmacological postconditioning: a molecular aspect in ischemic injury. J Pharm Pharmacol. 2020;72(11):1513–27. https://doi.org/10.1111/jphp.13336.

    Article  CAS  PubMed  Google Scholar 

  2. Soares RO, Losada DM, Jordani MC, Évora P, Castro-e-Silva O. Ischemia–reperfusion injury revisited: an overview of the latest pharmacological strategies. Int J Mol Sci. 2019;20(20):5034. https://doi.org/10.3390/ijms20205034.

    Article  CAS  PubMed Central  Google Scholar 

  3. Kalra P, Khan H, Kaur A, Singh TG. Mechanistic insight on autophagy modulated molecular pathways in cerebral ischemic injury: from preclinical to clinical perspective. Neurochem Res. 2022;7:1–9. https://doi.org/10.1007/s11064-021-03500-0.

    Article  CAS  Google Scholar 

  4. Phillis JW, Horrocks LA, Farooqui AA. Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev. 2006;52(2):201–43. https://doi.org/10.1016/j.brainresrev.2006.02.002.

    Article  CAS  PubMed  Google Scholar 

  5. Khan H, Gupta A, Singh TG, Kaur A. Mechanistic insight on the role of leukotriene receptors in ischemic–reperfusion injury. Pharmacol Rep. 2021;5:1–5. https://doi.org/10.1007/s43440-021-00258-8.

    Article  CAS  Google Scholar 

  6. Stachowicz K. Deciphering the mechanisms of regulation of an excitatory synapse via cyclooxygenase-2. A review Biochem Pharmacol. 2021;13: 114729. https://doi.org/10.1016/j.bcp.2021.114729.

    Article  CAS  Google Scholar 

  7. Irfan M. Selective cyclooxygenase-2 inhibitors: a review of recent chemical scaffolds with promising anti-inflammatory and COX-2 inhibitory activities. Med Chem Res. 2020;29(5):809–30. https://doi.org/10.1007/s00044-020-02528-1.

    Article  CAS  Google Scholar 

  8. Johnsson A, Choi JH, Rönnberg E, Fuchs D, Kolmert J, Hamberg M, Dahlén B, Wheelock CE, Dahlén SE, Nilsson G. COX-1 driven biosynthesis of PGD2 during activation of human mast cells prevents formation of other prostanoids. Eur Respiratory Soc. 2020. https://doi.org/10.1183/13993003.congress-2020.627.

    Article  Google Scholar 

  9. Li L, Sluter MN, Yu Y, Jiang J. Prostaglandin E receptors as targets for ischemic stroke: novel evidence and molecular mechanisms of efficacy. Pharmacol Res. 2020;11: 105238. https://doi.org/10.1016/j.phrs.2020.105238.

    Article  CAS  Google Scholar 

  10. Li L, Yu Y, Hou R, Hao J, Jiang J. Inhibiting the PGE2 receptor EP2 mitigates excitotoxicity and ischemic injury. ACS Pharmacol Transl Sci. 2020;3(4):635–43. https://doi.org/10.1021/acsptsci.0c00040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hou R, Yu Y, Jiang J. PGE2 receptors in detrusor muscle: drugging the undruggable for urgency. Biochem Pharmacol. 2021;1(184): 114363. https://doi.org/10.1016/j.bcp.2020.114363.

    Article  CAS  Google Scholar 

  12. Sluter MN, Hou R, Li L, Yasmen N, Yu Y, Liu J, Jiang J. EP2 Antagonists (2011–2021): a decade’s journey from discovery to therapeutics. J Med Chem. 2021;64(16):11816–36. https://doi.org/10.1021/acs.jmedchem.1c00816.

    Article  CAS  PubMed  Google Scholar 

  13. Yang C, Yang Y, DeMars KM, Rosenberg GA, Candelario-Jalil E. Genetic deletion or pharmacological inhibition of cyclooxygenase-2 reduces blood-brain barrier damage in experimental ischemic stroke. Front Neurol. 2020;20(11):887. https://doi.org/10.3389/fneur.2020.00887.

    Article  Google Scholar 

  14. Vishwakarma S, Singh S, Singh TG. Pharmacological modulation of cytokines correlating neuroinflammatory cascades in epileptogenesis. Mol Biol Rep. 2021. https://doi.org/10.1007/s11033-021-06896-8.

    Article  PubMed  Google Scholar 

  15. Xu Y, Liu Y, Li K, Miao S, Lv C, Wang C, Zhao J. Regulation of PGE2 Pathway During Cerebral Ischemia Reperfusion Injury in Rat. Cell Mol Neurobiol. 2021;41(7):1483–96. https://doi.org/10.1007/s10571-020-00911-5.

    Article  CAS  PubMed  Google Scholar 

  16. Thapa K, Khan H, Singh TG, Kaur A. Traumatic brain injury: mechanistic insight on pathophysiology and potential therapeutic targets. J Mol Neurosci. 2021;6:1–8. https://doi.org/10.1007/s12031-021-01841-7.

    Article  CAS  Google Scholar 

  17. Pawluk H, Woźniak A, Grześk G, Kołodziejska R, Kozakiewicz M, Kopkowska E, Grzechowiak E, Kozera G. The role of selected pro-inflammatory cytokines in pathogenesis of ischemic stroke. Clin Interv Aging. 2020;15:469. https://doi.org/10.2147/CIA.S233909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khan H, Sharma R, Kaur A, Singh TG. The endocannabinoids system and their implications in various disorders. Int J Pharm Sci Rev Res. 2018;367:3193–200.

    Google Scholar 

  19. Heysieattalab S, Doostmohammadi J, Darvishmolla M, Saeedi N, Hosseinmardi N, Gholami M, Janahmadi M, Choopani S. Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity. Naunyn-Schmiedeb Arch Pharmacol. 2021;3:1–3. https://doi.org/10.1007/s00210-021-02092-4.

    Article  CAS  Google Scholar 

  20. Khan H, Tiwari P, Kaur A, Singh TG. Sirtuin acetylation and deacetylation: a complex paradigm in neurodegenerative disease. Mol Neurobiol. 2021;20:1–5. https://doi.org/10.1007/s12035-021-02387-w.

    Article  CAS  Google Scholar 

  21. Nam GS, Park HJ, Nam KS. The antithrombotic effect of caffeic acid is associated with a cAMP-dependent pathway and clot retraction in human platelets. Thromb Res. 2020;1(195):87–94. https://doi.org/10.1016/j.thromres.2020.07.024.

    Article  CAS  Google Scholar 

  22. Singh S, Singh TG, Rehni AK, Sharma V, Singh M, Kaur R. Reviving mitochondrial bioenergetics: a relevant approach in epilepsy. Mitochondrion. 2021;58:213–26. https://doi.org/10.1016/j.mito.2021.03.009.

    Article  CAS  PubMed  Google Scholar 

  23. Md Idris MH, Mohd Amin SN, Mohd Amin SN, Wibowo A, Zakaria ZA, Shaameri Z, Hamzah AS, Selvaraj M, Teh LK, Salleh MZ. Discovery of polymethoxyflavones as potential cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and phosphodiesterase 4B (PDE4B) inhibitors. J Recept Signal Transduct Res. 2021;28:1–3. https://doi.org/10.1080/10799893.2021.1951756.

    Article  CAS  Google Scholar 

  24. Cheuk BL, Leung PS, Lo AC, Wong PY. Androgen control of cyclooxygenase expression in the rat epididymis. Biol Reprod. 2000;63(3):775–80. https://doi.org/10.1093/biolreprod/63.3.775.

    Article  CAS  PubMed  Google Scholar 

  25. Chanani NK, Cowan DB, Takeuchi K, Poutias DN, Garcia LM, del Nido PJ, McGowan FX Jr. Differential effects of amrinone and milrinone upon myocardial inflammatory signaling. Circulation. 2002;106(12):1–284. https://doi.org/10.1161/01.cir.0000032904.33237.8e.

    Article  CAS  Google Scholar 

  26. Fiebich BL, Biber K, Lieb K, Van Calker D, Berger M, Bauer J, Gebicke-Haerter PJ. Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2α-receptors. Glia. 1996;18(2):152–80. https://doi.org/10.1002/(SICI)1098-1136(199610)18:2%3c152::AID-GLIA7%3e3.0.CO;2-2.

    Article  CAS  PubMed  Google Scholar 

  27. Sharma VK, Singh TG. CREB: a multifaceted target for Alzheimer’s disease. Curr Alzheimer Res. 2020;17(14):1280–93. https://doi.org/10.2174/1567205018666210218152253.

    Article  CAS  PubMed  Google Scholar 

  28. Rm N, Klein T, Pfeilschifter J, Ullrich V. Effect of cyclic AMP and prostaglandin E2 on the induction of nitric oxide-and prostanoid-forming pathways in cultured rat mesangial cells. Biochem J. 1996;313(2):617–23. https://doi.org/10.1042/bj3130617.

    Article  Google Scholar 

  29. Maldve RE, Kim Y, Muga SJ, Fischer SM. Prostaglandin E2 regulation of cyclooxygenase expression in keratinocytes is mediated via cyclic nucleotide-linked prostaglandin receptors. J Lipid Res. 2000;41(6):873–81. https://doi.org/10.1016/S0022-2275(20)32029-0.

    Article  CAS  PubMed  Google Scholar 

  30. Tetradis SO, Pilbeam CC, Liu YO, Kream BE. Parathyroid hormone induces prostaglandin G/H synthase-2 expression by a cyclic adenosine 3’, 5’-monophosphate-mediated pathway in the murine osteoblastic cell line MC3T3-E1. Endocrinology. 1996;137(12):5435–40. https://doi.org/10.1210/endo.137.12.8940368.

    Article  CAS  PubMed  Google Scholar 

  31. Saklani P, Khan H, Gupta S, Kaur A, Singh TG. Neuropeptides: potential neuroprotective agents in ischemic injury. Life Sci. 2022;288: 120186. https://doi.org/10.1016/j.lfs.2021.120186.

    Article  CAS  PubMed  Google Scholar 

  32. Zhou XL, Lei ZM, Rao CV. Treatment of human endometrial gland epithelial cells with chorionic gonadotropin/luteinizing hormone increases the expression of the cyclooxygenase-2 gene. J Clin Endocrinol Metab. 1999;84(9):3364–77. https://doi.org/10.1210/jcem.84.9.5943.

    Article  CAS  PubMed  Google Scholar 

  33. Wong WY, DeWitt DL, Smith WL, Richards JS. Rapid induction of prostaglandin endoperoxide synthase in rat preovulatory follicles by luteinizing hormone and cAMP is blocked by inhibitors of transcription and translation. J Mol Endocrinol. 1989;3(11):1714–23. https://doi.org/10.1210/mend-3-11-1714.

    Article  CAS  Google Scholar 

  34. Al-kuraishy HM, Al-Gareeb AI. Vinpocetine and ischemic stroke. In: Ischemic stroke. London: IntechOpen; 2020. p. 103.

    Google Scholar 

  35. Zhao S, Cheng CK, Zhang CL, Huang Y. Interplay between oxidative stress, cyclooxygenases, and prostanoids in cardiovascular diseases. Antioxid Redox Signal. 2021;34(10):784–99. https://doi.org/10.1089/ars.2020.8105.

    Article  CAS  PubMed  Google Scholar 

  36. Khan H, Singh A, Thapa K, Garg N, Grewal AK, Singh TG. Therapeutic modulation of the phosphatidylinositol 3-kinases (PI3K) pathway in cerebral ischemic injury. Brain Res. 2021;15(1761): 147399. https://doi.org/10.1016/j.brainres.2021.147399.

    Article  CAS  Google Scholar 

  37. Zhang P, He D, Song E, Jiang M, Song Y. Celecoxib enhances the sensitivity of non-small-cell lung cancer cells to radiation-induced apoptosis through downregulation of the Akt/mTOR signaling pathway and COX-2 expression. PLoS ONE. 2019;14(10): e0223760. https://doi.org/10.1371/journal.pone.0223760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jendrossek V. Targeting apoptosis pathways by celecoxib in cancer. Cancer Lett. 2013;332(2):313–24. https://doi.org/10.1016/j.canlet.2011.01.012.

    Article  CAS  PubMed  Google Scholar 

  39. Gupta A, Khan H, Kaur A, Singh TG. Novel targets explored in the treatment of alcohol withdrawal syndrome. CNS Neurol Disord Drug Targets. 2020. https://doi.org/10.2174/1871527319999201118155721.

    Article  PubMed  Google Scholar 

  40. Hou CC, Hung SL, Kao SH, Chen TH, Lee HM. Celecoxib induces heme-oxygenase expression in glomerular mesangial cells. Ann N Y Acad Sci. 2005;1042(1):235–45. https://doi.org/10.1196/annals.1338.026.

    Article  CAS  PubMed  Google Scholar 

  41. Attuwaybi BO, Kozar RA, Moore-Olufemi SD, Sato N, Hassoun HT, Weisbrodt NW, Moore FA. Heme oxygenase-1 induction by hemin protects against gut ischemia/reperfusion injury1, 2. J Surg Res. 2004;118(1):53–7. https://doi.org/10.1016/j.jss.2004.01.010.

    Article  CAS  PubMed  Google Scholar 

  42. Ryter SW. Therapeutic potential of heme oxygenase-1 and carbon monoxide in acute organ injury, critical illness, and inflammatory disorders. Antioxidants. 2020;9(11):1153. https://doi.org/10.3390/antiox9111153.

    Article  CAS  PubMed Central  Google Scholar 

  43. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645–50. https://doi.org/10.1038/347645a0.

    Article  CAS  PubMed  Google Scholar 

  44. Mannan A, Garg N, Singh TG, Kang HK. Peroxisome proliferator-activated receptor-gamma (PPAR-ɣ): molecular effects and its importance as a novel therapeutic target for cerebral ischemic injury. Neurochem Res. 2021;20:1–32. https://doi.org/10.1007/s11064-021-03402-1.

    Article  CAS  Google Scholar 

  45. French JA, Koepp M, Naegelin Y, Vigevano F, Auvin S, Rho JM, Rosenberg E, Devinsky O, Olofsson PS, Dichter MA. Clinical studies and anti-inflammatory mechanisms of treatments. Epilepsia. 2017;58:69–82. https://doi.org/10.1111/epi.13779.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res. 2000;49(10):497–505.

    Article  CAS  Google Scholar 

  47. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci. 1994;91(15):7355–9. https://doi.org/10.1073/pnas.91.15.7355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aioi A. Peroxisome proliferator-activated receptors (PPARs) activation as therapeutic targets in skin inflammation. Trends Immunol. 2020;4(2):55–68.

    Google Scholar 

  49. Sato N, Kozar RA, Zou L, Weatherall JM, Attuwaybi B, Moore-Olufemi SD, Weisbrodt NW, Moore FA. Peroxisome proliferator-activated receptor γ mediates protection against cyclooxygenase-2-induced gut dysfunction in a rodent model of mesenteric ischemia/reperfusion. Shock. 2005;24(5):462–9. https://doi.org/10.1097/01.shk.0000183483.76972.ae.

    Article  CAS  PubMed  Google Scholar 

  50. Liu L, He YR, Liu SJ, Hu L, Liang LC, Liu DL, Liu L, Zhu ZQ. Enhanced effect of IL-1β-activated adipose-derived MSCs (ADMSCs) on repair of intestinal ischemia–reperfusion injury via COX-2-PGE2 signaling. Stem Cells Int. 2020;17:2020. https://doi.org/10.1155/2020/2803747.

    Article  CAS  Google Scholar 

  51. El-Shitany NA, Eid BG. Icariin modulates carrageenan-induced acute inflammation through HO-1/Nrf2 and NF-kB signaling pathways. Biomed Pharmacother. 2019;1(120): 109567. https://doi.org/10.1016/j.biopha.2019.109567.

    Article  CAS  Google Scholar 

  52. Chen LW, Egan L, Li ZW, Greten FR, Kagnoff MF, Karin M. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia–reperfusion. Nat Med. 2003;9(5):575–81. https://doi.org/10.1038/nm849.

    Article  CAS  PubMed  Google Scholar 

  53. Hu YF, Guo Y, Cheng GF. Inhibitory effects of indomethacin and meloxicam on NF-kappa B in mouse peritoneal macrophages. Acta Pharm Sin B. 2001;36(3):161–4.

    CAS  Google Scholar 

  54. Dorrington MG, Fraser ID. NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Front Immunol. 2019;9(10):705. https://doi.org/10.3389/fimmu.2019.00705.

    Article  CAS  Google Scholar 

  55. Li LC, Hou Q, Guo Y, Cheng GF. Inhibitory effect of meloxicam on human polymorphonuclear leukocyte adhesion to human synovial cell. Acta Pharm Sin B. 2002;37(2):103–7.

    CAS  Google Scholar 

  56. Little D, Jones SL, Blikslager AT. Cyclooxygenase (COX) inhibitors and the intestine. J Vet Intern Med. 2007;21(3):367–77. https://doi.org/10.1111/j.1939-1676.2007.tb02978.x.

    Article  PubMed  Google Scholar 

  57. Lee S, Shin S, Kim H, Han S, Kim K, Kwon J, Kwak JH, Lee CK, Ha NJ, Yim D, Kim K. Anti-inflammatory function of arctiin by inhibiting COX-2 expression via NF-κB pathways. J Inflamm. 2011;8(1):1–9. https://doi.org/10.1186/1476-9255-8-16.

    Article  CAS  Google Scholar 

  58. Kwon DJ, Ju SM, Youn GS, Choi SY, Park J. Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF-κB and AP-1 activation in RAW 264.7 macrophages. Food Chem Toxicol. 2013;58:479–86. https://doi.org/10.1016/j.fct.2013.05.031.

    Article  CAS  PubMed  Google Scholar 

  59. Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16(1):1–24. https://doi.org/10.1186/s12974-019-1516-2.

    Article  Google Scholar 

  60. Iwasa K, Yamamoto S, Yagishita S, Maruyama K, Yoshikawa K. Excitotoxicity-induced prostaglandin D2 production induces sustained microglial activation and delayed neuronal death. J Lipid Res. 2017;58(4):649–55. https://doi.org/10.1194/jlr.M070532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Huang H, Al-Shabrawey M, Wang MH. Cyclooxygenase-and cytochrome P450-derived eicosanoids in stroke. Prostaglandins Other Lipid Mediat. 2016;1(122):45–53. https://doi.org/10.1016/j.prostaglandins.2015.12.007.

    Article  CAS  Google Scholar 

  62. Ghazanfari N, van Waarde A, Dierckx RA, Doorduin J, de Vries EF. Is cyclooxygenase-1 involved in neuroinflammation? J Neurosci Res. 2021. https://doi.org/10.1002/jnr.24934.

    Article  PubMed  Google Scholar 

  63. Liu R, Wu S, Guo C, Hu Z, Peng J, Guo K, Zhang X, Li J. Ibuprofen exerts antiepileptic and neuroprotective effects in the rat model of pentylenetetrazol-induced epilepsy via the COX-2/NLRP3/IL-18 pathway. Neurochem Res. 2020;45(10):2516–26. https://doi.org/10.1007/s11064-020-03109-9.

    Article  CAS  PubMed  Google Scholar 

  64. Antezana DF, Clatterbuck RE, Alkayed NJ, Murphy SJ, Anderson LG, Frazier J, Hurn PD, Traystman RJ, Tamargo RJ. High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats. J Neurosurg. 2003;98(4):860–6. https://doi.org/10.3171/jns.2003.98.4.0860.

    Article  CAS  PubMed  Google Scholar 

  65. Vahid S, Hassan EV, Abbas S, Mehdi A, Reza M, Behzad B, Abedin V. Neuroprotective effect of post ischemic treatment of acetylsalicylic acid on CA1 Hippocampus neuron and spatial learning in transient MCA occlusion in ratJ. Med Sci (Faisalabad). 2008;8(4):357–63.

    Google Scholar 

  66. Berger C, Stauder A, Xia F, Sommer C, Schwab S. Neuroprotection and glutamate attenuation by acetylsalicylic acid in temporary but not in permanent cerebral ischemia. Exp Neurol. 2008;210(2):543–8. https://doi.org/10.1016/j.expneurol.2007.12.002.

    Article  CAS  PubMed  Google Scholar 

  67. Zheng Z, Schwab S, Grau A, Berger C. Neuroprotection by early and delayed treatment of acute stroke with high dose aspirin. Brain Res. 2007;19(1186):275–80. https://doi.org/10.1016/j.brainres.2007.10.029.

    Article  CAS  Google Scholar 

  68. Yamamoto N, Yokota K, Yamashita A, Oda M. Effect of KBT-3022, a new cyclooxygenase inhibitor, on experimental brain edema in vitro and in vivo. Eur J Pharmacol. 1996;297(3):225–31. https://doi.org/10.1016/0014-2999(95)00777-6.

    Article  CAS  PubMed  Google Scholar 

  69. Galvão RI, Diógenes JP, Maia GC, Emídio Filho AS, Vasconcelos SM, de Menezes DB, Cunha GM, Viana GS. Tenoxicam exerts a neuroprotective action after cerebral ischemia in rats. Neurochem Res. 2005;30(1):39–46. https://doi.org/10.1007/s11064-004-9684-5.

    Article  CAS  PubMed  Google Scholar 

  70. Li W, Wu S, Hickey RW, Rose ME, Chen J, Graham SH. Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2α exacerbate hypoxic neuronal injury in neuron-enriched primary culture. Neurochem Res. 2008;33(3):490–9. https://doi.org/10.1007/s11064-007-9462-2.

    Article  CAS  PubMed  Google Scholar 

  71. Liu Q, Liang X, Wang Q, Wilson EN, Lam R, Wang J, Kong W, Tsai C, Pan T, Larkin PB, Shamloo M. PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proc Natl Acad Sci. 2019;116(20):10019–24. https://doi.org/10.1073/pnas.1818544116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ayer R, Jadhav V, Sugawara T, Zhang JH. The neuroprotective effects of cyclooxygenase-2 inhibition in a mouse model of aneurysmal subarachnoid hemorrhage. In: Intracerebral hemorrhage research. Vienna: Springer; 2011. p. 145–9.

    Chapter  Google Scholar 

  73. Govoni S, Masoero E, Favalli L, Rozza A, Scelsi R, Viappiani S, Buccellati C, Sala A, Folco G. The cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat. Neurosci Lett. 2001;303(2):91–4. https://doi.org/10.1016/S0304-3940(01)01675-5.

    Article  CAS  PubMed  Google Scholar 

  74. Holtman L, van Vliet EA, Van Schaik R, Queiroz CM, Aronica E, Gorter JA. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res. 2009;84(1):56–66. https://doi.org/10.1016/j.eplepsyres.2008.12.006.

    Article  CAS  PubMed  Google Scholar 

  75. Kelsen J, Kjær K, Chen G, Pedersen M, Røhl L, Frøkiær J, Nielsen S, Nyengaard JR, Rønn LC. Parecoxib is neuroprotective in spontaneously hypertensive rats after transient middle cerebral artery occlusion: a divided treatment response? J Neuroinflamm. 2006;3(1):1–9. https://doi.org/10.1186/1742-2094-3-31.

    Article  CAS  Google Scholar 

  76. Abdel-Gaber SA, Ibrahim MA, Amin EF, Ibrahim SA, Mohammed RK, Abdelrahman AM. Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia–reperfusion-induced hepatic injury in rats. Life sci. 2015;1(134):42–8. https://doi.org/10.1016/j.lfs.2015.04.025.

    Article  CAS  Google Scholar 

  77. Takeuchi K, Komatsu Y, Nakamori Y, Kotani T. A rat model of ischemic enteritis: pathogenic importance of enterobacteria, iNOS/NO, and COX-2/PGE2. Curr Pharm Des. 2017;23(27):4048–56. https://doi.org/10.2174/1381612823666170220154815.

    Article  CAS  PubMed  Google Scholar 

  78. Sanchez-Matienzo D, Arana A, Castellsague J, Perez-Gutthann S. Hepatic disorders in patients treated with COX-2 selective inhibitors or nonselective NSAIDs: a case/noncase analysis of spontaneous reports. Clin Ther. 2006;28(8):1123–32. https://doi.org/10.1016/j.clinthera.2006.08.014.

    Article  CAS  PubMed  Google Scholar 

  79. Yu J, Ip E, dela Peña A, Hou JY, Sesha J, Pera N, Hall P, Kirsch R, Leclercq I, Farrell GC. COX-2 induction in mice with experimental nutritional steatohepatitis: role as pro-inflammatory mediator. Hepatology. 2006;43(4):826–36. https://doi.org/10.1002/hep.21108.

    Article  CAS  PubMed  Google Scholar 

  80. Oshima K, Yabata Y, Yoshinari D, Takeyoshi I. The effects of cyclooxygenase (COX)-2 inhibition on ischemia–reperfusion injury in liver transplantation. J Invest Surg. 2009;22(4):239–45. https://doi.org/10.1080/08941930903040080.

    Article  PubMed  Google Scholar 

  81. Sunose Y, Takeyoshi I, Ohwada S, Tsutsumi H, Iwazaki S, Kawata K, Kawashima Y, Tomizawa N, Matsumoto K, Morishita Y. The effect of cyclooxygenase-2 inhibitor FK3311 on ischemia–reperfusion injury in a canine total hepatic vascular exclusion model. J Am Coll Surg. 2001;192(1):54–62. https://doi.org/10.1016/S1072-7515(00)00773-0.

    Article  CAS  PubMed  Google Scholar 

  82. Xiao ZY, Banan B, Jia J, Manning PT, Hiebsch RR, Gunasekaran M, Upadhya GA, Frazier WA, Mohanakumar T, Lin Y, Chapman WC. CD47 blockade reduces ischemia/reperfusion injury and improves survival in a rat liver transplantation model. Liver Transpl. 2015;21(4):468–77. https://doi.org/10.1002/lt.24059.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Fu H, Chen H, Wang C, Xu H, Liu F, Guo M, Wang Q, Shi X. Flurbiprofen, a cyclooxygenase inhibitor, protects mice from hepatic ischemia/reperfusion injury by inhibiting GSK-3β signaling and mitochondrial permeability transition. Mol Med. 2012;18(7):1128–35. https://doi.org/10.2119/molmed.2012.00088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhang T, Ma Y, Xu KQ, Huang WQ. Pretreatment of parecoxib attenuates hepatic ischemia/reperfusion injury in rats. BMC Anesthesiol. 2015;15(1):1–8. https://doi.org/10.1186/s12871-015-0147-0.

    Article  CAS  Google Scholar 

  85. Tolba RH, Fet N, Yonezawa K, Taura K, Nakajima A, Hata K, Okamura Y, Uchinami H, Klinge U, Minor T, Yamaoka Y. Role of preferential cyclooxygenase-2 inhibition by meloxicam in ischemia/reperfusion injury of the rat liver. Eur Surg Res. 2014;53(1–4):11–24. https://doi.org/10.1159/000362411.

    Article  CAS  PubMed  Google Scholar 

  86. Jia Z, Zhang Y, Ding G, Heiney KM, Huang S, Zhang A. Role of COX-2/mPGES-1/prostaglandin E2 cascade in kidney injury. Mediat Inflamm. 2015. https://doi.org/10.1155/2015/147894.

    Article  Google Scholar 

  87. Mederle K, Meurer M, Castrop H, Höcherl K. Inhibition of COX-1 attenuates the formation of thromboxane A2 and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice. Am J Physiol Renal Physiol. 2015;309(4):F332–40. https://doi.org/10.1152/ajprenal.00567.2014.

    Article  CAS  PubMed  Google Scholar 

  88. Lomas AL, Grauer GF. The renal effects of NSAIDs in dogs. J Am Anim Hosp Assoc. 2015;51(3):197–203. https://doi.org/10.5326/JAAHA-MS-6239.

    Article  PubMed  Google Scholar 

  89. Suemanotham N. Cyclooxygenase enzymes expression in the kidney. Appl Anim Sci. 2014;7(3):9–22.

    Google Scholar 

  90. Kim MJ, Shrestha SS, Cortes M, Singh P, Morse C, Liow JS, Gladding RL, Brouwer C, Henry K, Gallagher E, Tye GL. Evaluation of two potent and selective PET radioligands to image COX-1 and COX-2 in rhesus monkeys. J Nucl Med. 2018;59(12):1907–12. https://doi.org/10.2967/jnumed.118.211144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Calistro JP, Torres RD, Gonçalves GM, Silva LM, Domingues MA, Módolo NS, Barros GA. Parecoxib reduces renal injury in an ischemia/reperfusion model in rats1. Acta Cir Bras. 2015;30:270–6. https://doi.org/10.1590/S0102-865020150040000006.

    Article  Google Scholar 

  92. Knight S, Johns EJ. Effect of COX inhibitors and NO on renal hemodynamics following ischemia–reperfusion injury in normotensive and hypertensive rats. Am J Physiol Renal Physiol. 2005;289(5):F1072–7. https://doi.org/10.1152/ajprenal.00430.2004.

    Article  CAS  PubMed  Google Scholar 

  93. Yun Y, Duan WG, Chen P, Wu HX, Shen ZQ, Qian ZY, Wang DH. Down-regulation of cyclooxygenase-2 is involved in ischemic postconditioning protection against renal ischemia reperfusion injury in rats. Transpl Proc. 2009;41(9):3585–9. https://doi.org/10.1016/j.transproceed.2009.06.209.

    Article  CAS  Google Scholar 

  94. Bischoff A, Bucher M, Gekle M, Sauvant C. Differential effect of COX1 and COX2 inhibitors on renal outcomes following ischemic acute kidney injury. Am J Nephrol. 2014;40(1):1–1. https://doi.org/10.1159/000363251.

    Article  CAS  PubMed  Google Scholar 

  95. Schneider R, Meusel M, Renker S, Bauer C, Holzinger H, Roeder M, Wanner C, Gekle M, Sauvant C. Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome. Am J Physiol Renal Physiol. 2009;297(6):F1614–21. https://doi.org/10.1152/ajprenal.00268.2009.

    Article  CAS  PubMed  Google Scholar 

  96. Zhu SH, Zhou LJ, Jiang H, Chen RJ, Lin C, Feng S, Jin J, Chen JH, Wu JY. Protective effect of indomethacin in renal ischemia–reperfusion injury in mice. J Zhejiang Univ Sci B. 2014;15(8):735–42. https://doi.org/10.1631/jzus.B1300196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Senbel AM, AbdelMoneim L, Omar AG. Celecoxib modulates nitric oxide and reactive oxygen species in kidney ischemia/reperfusion injury and rat aorta model of hypoxia/reoxygenation. Curr Vasc Pharmacol. 2014;62(1):24–31. https://doi.org/10.1016/j.vph.2014.04.004.

    Article  CAS  Google Scholar 

  98. Cox A, Varma A, Banik N. Recent advances in the pharmacologic treatment of spinal cord injury. Metab Brain Dis. 2015;30(2):473–82. https://doi.org/10.1007/s11011-014-9547-y.

    Article  CAS  PubMed  Google Scholar 

  99. Zhu X, Eisenach JC. Cyclooxygenase-1 in the spinal cord is altered after peripheral nerve injury. Int J Anesth Anesthesiol. 2003;99(5):1175–9. https://doi.org/10.1097/00000542-200311000-00026.

    Article  CAS  Google Scholar 

  100. Hurley SD, Olschowka JA, O’Banion MK. Cyclooxygenase inhibition as a strategy to ameliorate brain injury. J Neurotrauma. 2002;19(1):1–5. https://doi.org/10.1089/089771502753460196.

    Article  PubMed  Google Scholar 

  101. Rehni AK, Singh TG, Singh N, Arora S. Tramadol-induced seizurogenic effect: a possible role of opioid-dependent histamine (H 1) receptor activation-linked mechanism. Naunyn-Schmiedeb Arch Pharmacol. 2010;381(1):11. https://doi.org/10.1007/s00210-009-0476-y.

    Article  CAS  Google Scholar 

  102. Aghazadeh-Habashi A, Asghar W, Jamali F. Drug-disease interaction: effect of inflammation and nonsteroidal anti-inflammatory drugs on cytochrome P450 metabolites of arachidonic acid. J Pharm Sci. 2018;107(2):756–63. https://doi.org/10.1016/j.xphs.2017.09.020.

    Article  CAS  PubMed  Google Scholar 

  103. Braughler JM, Hall ED. Central nervous systems trauma and stroke: I. Biochemical considerations for oxygen radical formation and lipid peroxidation. Free Radic Biol Med. 1989;6(3):289–301. https://doi.org/10.1016/0891-5849(89)90056-7.

    Article  CAS  PubMed  Google Scholar 

  104. Sharma VK, Singh TG. Navigating Alzheimer’s disease via chronic stress: the role of glucocorticoids. Curr Drug Targets. 2020;21(5):433–44. https://doi.org/10.2174/1389450120666191017114735.

    Article  CAS  PubMed  Google Scholar 

  105. Basu S, Hellberg A, Ulus AT, Westman J, Karacagil S. Biomarkers of free radical injury during spinal cord ischemia. FEBS Lett. 2001;508(1):36–8. https://doi.org/10.1016/S0014-5793(01)02998-2.

    Article  CAS  PubMed  Google Scholar 

  106. Resnick DW, Graham SH, Dixon CE, Marion DW. Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma. 1998;15(12):1005–13.

    Article  CAS  Google Scholar 

  107. Hains BC, Yucra JA, Hulsebosch CE. Reduction of pathological and behavioral deficits following spinal cord contusion injury with the selective cyclooxygenase-2 inhibitor NS-398. J Neurotrauma. 2001;18(4):409–23. https://doi.org/10.1089/089771501750170994.

    Article  CAS  PubMed  Google Scholar 

  108. Hsieh YC, Liang WY, Tsai SK, Wong CS. Intrathecal ketorolac pretreatment reduced spinal cord ischemic injury in rats. Anesth Analg. 2005;100(4):1134–9. https://doi.org/10.1213/01.ANE.0000146962.91038.15.

    Article  CAS  PubMed  Google Scholar 

  109. Lapchak PA, Araujo DM, Song D, Zivin JA. Neuroprotection by the selective cyclooxygenase-2 inhibitor SC-236 results in improvements in behavioral deficits induced by reversible spinal cord ischemia. Stroke. 2001;32(5):1220–5. https://doi.org/10.1161/01.STR.32.5.1220.

    Article  CAS  PubMed  Google Scholar 

  110. LaPointe MC, Mendez M, Leung A, Tao Z, Yang XP. Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse. Am J Physiol Heart Circ. 2004;286(4):H1416–24. https://doi.org/10.1152/ajpheart.00136.2003.

    Article  CAS  Google Scholar 

  111. Bouchard JF, Lamontagne D. Mechanisms of protection afforded by cyclooxygenase inhibitors to endothelial function against ischemic injury in rat isolated hearts. J Cardiovasc Pharmacol. 1999;34(5):755–63.

    Article  CAS  Google Scholar 

  112. Martín Arias LH, Martín González A, Sanz Fadrique R, Vazquez ES. Cardiovascular risk of nonsteroidal anti-inflammatory drugs and classical and selective cyclooxygenase-2 inhibitors: a meta-analysis of observational studies. J Clin Pharmacol. 2019;59(1):55–73. https://doi.org/10.1002/jcph.1302.

    Article  CAS  PubMed  Google Scholar 

  113. Marqués J, Cortés A, Pejenaute Á, Ansorena E, Abizanda G, Prósper F, Martínez-Irujo JJ, Miguel CD, Zalba G. Induction of cyclooxygenase-2 by overexpression of the human NADPH oxidase 5 (NOX5) gene in aortic endothelial cells. Cells. 2020;9(3):637. https://doi.org/10.3390/cells9030637.

    Article  CAS  PubMed Central  Google Scholar 

  114. Pang L, Cai Y, Tang EH, Irwin MG, Ma H, Xia Z. Prostaglandin E receptor subtype 4 signaling in the heart: role in ischemia/reperfusion injury and cardiac hypertrophy. J Diabetes Res. 2016;13:2016. https://doi.org/10.1155/2016/1324347.

    Article  CAS  Google Scholar 

  115. Rossoni G, Muscara MN, Cirino G, Wallace JL. Inhibition of cyclo-oxygenase-2 exacerbates ischaemia-induced acute myocardial dysfunction in the rabbit. Br J Pharmacol. 2002;135(6):1540–6. https://doi.org/10.1038/sj.bjp.0704585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Scheuren N, Jacobs M, Ertl G, Schorb W. Cyclooxygenase-2 in myocardium stimulation by angiotensin-II in cultured cardiac fibroblasts and role at acute myocardial infarction. J Mol Cell Cardiol. 2002;34(1):29–37. https://doi.org/10.1006/jmcc.2001.1484.

    Article  CAS  PubMed  Google Scholar 

  117. Zhao Y, Zheng Q, Gao H, Cao M, Wang H, Chang R, Zeng C. Celecoxib alleviates pathological cardiac hypertrophy and fibrosis via M1-like macrophage infiltration in neonatal mice. Iscience. 2021;24(3): 102233. https://doi.org/10.1016/j.isci.2021.102233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ucar BI, Erikci A, Kosemehmetoglu K, Ozkul C, Iskit AB, Ucar G, Zeren S. Effects of endothelin receptor blockade and COX inhibition on intestinal I/R injury in a rat model: Experimental research. Int J Surg Open. 2020;1(83):89–97. https://doi.org/10.1016/j.ijsu.2020.08.061.

    Article  Google Scholar 

  119. Sun L. Low-dose cyclooxygenase-2 (COX-2) inhibitor celecoxib plays a protective role in the rat model of neonatal necrotizing enterocolitis. Bioengineered. 2021;12(1):7234–45. https://doi.org/10.1080/21655979.2021.1980646.

    Article  CAS  PubMed  Google Scholar 

  120. Huang Z, Ma X, Jia X, Wang R, Liu L, Zhang M, Wan X, Tang C, Huang L. Prevention of severe acute pancreatitis with cyclooxygenase-2 inhibitors: a randomized controlled clinical trial. Am J Gastroenterol Suppl. 2020;115(3):473. https://doi.org/10.14309/ajg.0000000000000529.

    Article  Google Scholar 

  121. Tong F, Dong B, Chai R, Tong K, Wang Y, Chen S, Zhou X, Liu D. Simvastatin nanoparticles attenuated intestinal ischemia/reperfusion injury by downregulating BMP4/COX-2 pathway in rats. Int J Nanomedicine. 2017;12:2477. https://doi.org/10.2147/IJN.S126063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India, for providing the necessary facilities to carry out the research work.

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  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Heena Khan, Kunal Sharma, Amit Kumar, Amarjot Kaur & Thakur Gurjeet Singh

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  1. Heena Khan
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  2. Kunal Sharma
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  3. Amit Kumar
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Conceptualization, conceived and designed the experiments: TGS. Analyzed the data: AK and TGS. Wrote the manuscript: HK and KS. Visualization: HK and AK. Editing of the Manuscript: HK, TGS. Critically reviewed the article: AK and TGS. Supervision: TGS. All authors read and approved the final manuscript.

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Correspondence to Thakur Gurjeet Singh.

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Khan, H., Sharma, K., Kumar, A. et al. Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury. Inflamm. Res. 71, 277–292 (2022). https://doi.org/10.1007/s00011-022-01546-6

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