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COX-1 and COX-2 polymorphisms in susceptibility to cerebral palsy in very preterm infants

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Abstract

Cerebral palsy (CP) is a nonprogressive motor disorder caused by white matter damage in the developing brain. Recent epidemiological and clinical data suggest intrauterine infection/inflammation as the most common cause of preterm delivery and neonatal complications, including CP. Cyclooxygenases are key enzymes in the conversion of arachidonic acid to prostaglandins. The COX family consists of two isoforms, COX-1 and COX-2. In the brain, COX-2 is constitutively expressed at high levels on pyramidal neurons, while COX-1 is predominantly expressed by microglia and can be upregulated in pathological conditions, such as infection, ischemia and traumatic brain injury. Single nucleotide polymorphisms in the COX-1 and COX-2 gene could have profound effects on COX-1 and COX-2 expression and, directly or indirectly, influence the pathogenesis, development and severity of CP. In this study we investigated the association between single nucleotide polymorphisms of the COX-1 and COX-2 gene and susceptibility to cerebral palsy in very preterm infants. The results of our study showed the association between COX-1 high expression genotype (−842 AA) and COX-1 high expression allele −842A and risk of CP in infants with cystic periventricular leucomalacia (cPVL). Our results support an important role of COX-1 enzyme on microglial activation during neuroinflammation resulting in huge neuroinflammatory response and the proinflammatory mediator overproduction, with the serious white matter damage and CP development as a consequence.

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References

  1. Oskoui M, Coutinho F, Dykeman J, Jetté N, Pringsheim T (2013) An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol 55:509–519. doi:10.1111/dmcn.12080v

    Article  PubMed  Google Scholar 

  2. Arpino C, D'Argenzio L, Ticconi C, Di Paolo A, Stellin V, Lopez L, Curatolo P (2005) Brain damage in preterm infants: etiological pathways. Ann Ist Super Sanita 41:229–237

    CAS  PubMed  Google Scholar 

  3. Volpe JJ (2001) Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 2001(50):553–562. doi:10.1203/00006450-200111000-00003

    Article  Google Scholar 

  4. Rezaie P, Dean A (2002) Periventricular leucomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 22:106–132. doi:10.1046/j.1440-1789.2002.00438.x

    Article  PubMed  Google Scholar 

  5. Khwaya O, Volpe JJ (2008) Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 93:F153–F161. doi:10.1136/adc.2006.1008837

    Article  Google Scholar 

  6. Bashiri A, Burstein E, Mazor M (2006) Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med 34:5–12. doi:10.1515/JPM.2006.001

    Article  PubMed  Google Scholar 

  7. Malaeb S, Dammann O (2009) Fetal inflammatory response and brain injury in the preterm newborn. J Child Neurol 24:1119–1126. doi:10.1177/0883073809338066

    Article  PubMed  PubMed Central  Google Scholar 

  8. Farooqui AA, Horrocks LA, Farooqui T (2007) Modulation of inflammation in brain: a matter of fat. J Neurochem 101:577–599. doi:10.1111/j.1471-4159.2006.04371.x

    Article  CAS  PubMed  Google Scholar 

  9. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69. doi:10.1038/nrn2038

    Article  CAS  PubMed  Google Scholar 

  10. Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Phil Trans R Soc Lond B Biol Sci 358:1669–1677. doi:10.1098/rstb.2003.1358

    Article  CAS  Google Scholar 

  11. Choi SH, Langenbach R, Bosetti F (2006) Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-kB pathway and downstream enzymes involved in prostaglandin biosynthesis. J Neurochem 98:801–811. doi:10.1111/j.1471-4159.2006.03926.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sreeramkumar V, Fresno M, Cuest N (2012) Prostaglandin E2 and T cells: friends or foes? Immunol Cell Biol 90:579–586. doi:10.1038/icb.2011.75

    Article  CAS  PubMed  Google Scholar 

  13. Candelario-Jalil E, Taheri YY, Sood R, Grossetete M, Estrada EY, Fiebich BL, Rosenberg GA (2007) Cyclooxygenase inhibition limits blood–brain barrier disruption following intracerebral injection of tumor necrosis factor-α in the rat. J Pharmacol Exp Ther 323:488–498. doi:10.1124/jpet.107.127035

    Article  CAS  PubMed  Google Scholar 

  14. Choi SH, Langenbach R, Bosetti F (2008) Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. FASEB J 22:1491–1501. doi:10.1096/fj.07-9411com

    Article  CAS  PubMed  Google Scholar 

  15. Morteau O (2000) Prostaglandins and inflammation:the cyclooxygenase controversy. Arch Immunol Ther Exp (Warsz) 48:473–480

    CAS  Google Scholar 

  16. Halushka MK, Walker LP, Halushka PV (2003) Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin Pharmacol Ther 73:122–130. doi:10.1067/mcp.2003.1

    Article  CAS  PubMed  Google Scholar 

  17. Shi J, Misso NLA, Duffy DL, Bradley B, Beard R, Thompson PJ, Kedda MA (2005) Cyclooxygenase-1 gene polymorphisms in patients with different asthma phenotypes and atopy. Eur Respir J 26:249–256. doi:10.1183/09031936.05.00140104

    Article  CAS  PubMed  Google Scholar 

  18. Akkiz H, Bayram S, Bekar A, Akgollu E, Ulger Y (2011) Functional polymorphisms of cyclooxygenase-2 gene and risk for hepatocellular carcinoma. Mol Cell Biochem 347:201–208. doi:10.1007/s11010-010-0629-9

    Article  CAS  PubMed  Google Scholar 

  19. Zhang X, Miao X, Tan W, Ning B, Liu Z, Hong Y, Song W, Guo Y, Zhang X, Shen Y, Qiang B, Kadlubar FF, Lin D (2005) Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology 129:565–576. doi:10.1053/j.gastro.2005.05.003

    CAS  PubMed  Google Scholar 

  20. Cok SJ, Morrison AR (2001) The 3′-untranslated region of murine cyclooxygenase contains multiple regulatory elements that alter message stability and transcriptional efficiency. J Biol Chem 276:23179–23185. doi:10.1074/jbc.M008461200

    Article  CAS  PubMed  Google Scholar 

  21. Sanak M, Szczeklik W, Szczeklik A (2005) Association of COX-2 gene haplotypes with prostaglandins production in bronchial asthma. J Allergy Clin Immunol 116:221–223. doi:10.1016/j.jaci.2005.03.010

    Article  CAS  PubMed  Google Scholar 

  22. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, Kim IO (1997) Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1β and tumor necrosis factor-α), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 177:19–26. doi:10.1016/S0002-9378(97)70432-0

    Article  CAS  PubMed  Google Scholar 

  23. Favrais G, Schwendimann L, Gressens P, Leliévre V (2007) Cyclooxygenase-2 mediates the sensitizing effects of systemic IL-1-beta on excitotoxic brain lesions in newborn mice. Neurobiology of Disease 25:496–505

    Article  CAS  PubMed  Google Scholar 

  24. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18. doi:10.1016/j.neuron.2012.12.023

    Article  CAS  PubMed  Google Scholar 

  25. Kempermann G, Neumann H (2003) Neuroscience. Microglia: the enemy within? Science 302:1689–1690. doi:10.1126/science.1092864

    Article  CAS  PubMed  Google Scholar 

  26. Phillips JW, Horrocks LA, Farooqui AA (2006) Cyclooxygenases, lipoxygenases and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev 52:201–243. doi:10.1016/j.brainresrev.2006.02.002

    Article  Google Scholar 

  27. Kapitanović Vidak H, Catela Ivković T, Jokić M, Spaventi R, Kapitanović S (2012) The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants. Cytokine 58:57–64. doi:10.1016/j.cyto.2011.12.018

    Article  PubMed  Google Scholar 

  28. Milatovic D, Montine TJ, Aschner M (2011) Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity. Neurotoxicology 32:312–319. doi:10.1016/j.neuro.2011.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular and molecular biology. Annu Rev Biochem 69:145–182. doi:10.1146/annurev.biochem.69.1.145

    Article  CAS  PubMed  Google Scholar 

  30. Xu XM, Tang JL, Chen X, Wang LH, Wu KK (1997) Involvement of two Sp1 elements in basal endothelial prostaglandin H synthase-1 promoter activity. J Biol Chem 272:6943–6950. doi:10.1074/jbc.272.11.6943

    Article  CAS  PubMed  Google Scholar 

  31. Ulrich CM, Bigler J, Silbert J, Greene EA, Sparks R, Carlson CS, Potter JD (2002) Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations. Hum Mutation 20:409–410. doi:10.1002/humu.9080

    Article  Google Scholar 

  32. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, Laurent GJ (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22:1631–1636. doi:10.1161/01.ATV.0000030340.80207.C5

    Article  CAS  PubMed  Google Scholar 

  33. Li M, Gao Y, Li C, Liu L, Li K, Gao L, Wang G, Zhang Z, Gao T (2009) Association of COX2 functional polymorphisms and the risk of vitiligo in Chinese populations. J Dermatol Science 53:176–181. doi:10.1016/j.jdermsci.2008.09.010

    Article  CAS  Google Scholar 

  34. Choi SH, Aid S, Bosetti F (2009) The distinct roles of cyclooxigenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30:174–181. doi:10.1016/j.tips.2009.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pepicelli O, Fedele E, Berardi M, Raiteri M, Levi G, Greco A, Ajmone-Cat MA, Minghetti L (2005) Cyclooxygenase-1 and -2 differently contribute to prostaglandin E2 synthesis and lipid peroxidation after in vivo activation of N-methyl-D-aspartate receptors in rat hippocampus. J Neurochem 93:1561–1567. doi:10.1111/j.1471-4159.2005.03150.x

    Article  CAS  PubMed  Google Scholar 

  36. Calvello R, Panaro MA, Carbone ML, Cianciulli A, Perrone MG, Vitale P, Malerba P, Scilimati A (2012) Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells. Pharmacol Res 65:137–148. doi:10.1016/j.phrs.2011.09.009

    Article  CAS  PubMed  Google Scholar 

  37. Aid S, Silva AC, Candelario-Jajil E, Choi SH, Rosenberg GA, Bosetti F (2010) Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood–brain barrier disruption through matrix metalloproteinase activity. J Cereb Blood Flow Metab 30:370–380. doi:10.1038/jcbfm.2009.223

    Article  CAS  PubMed  Google Scholar 

  38. Aid S, Langenbach R, Bosetti F (2008) Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation 5:17. doi:10.1186/1742-2094-5-17

    Article  PubMed  PubMed Central  Google Scholar 

  39. Serhan CN (2007) Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol 25:101–137. doi:10.1146/annurev.immunol.25.022106.141647

    Article  CAS  PubMed  Google Scholar 

  40. Levy BD (2010) Resolvins and protectins: natural pharmacophores for resolution biology. Prostaglandins Leukot Essent Fatty Acids 82:327–332. doi:10.1016/j.plefa.2010.02.0003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Choi SH, Aid S, Choi U, Bosetti F (2010) Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenomics J 10:448–457. doi:10.1038/tpj.2009.68

    Article  CAS  PubMed  Google Scholar 

  42. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA (1999) Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 5:698–701. doi:10.1038/9550

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Special Hospital for Children with Neurodevelopmental and Motor Difficulties, Goljak 2, Zagreb, Croatia

    Helena Kapitanović Vidak

  2. Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička c. 54, Zagreb, Croatia

    Tina Catela Ivković & Sanja Kapitanović

  3. Department of Obstetrics and Gynecology, Division of Neonatology, Clinical Hospital Merkur, Ivana Zajca 19, Zagreb, Croatia

    Zoran Vidak

Authors
  1. Helena Kapitanović Vidak
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  2. Tina Catela Ivković
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  3. Zoran Vidak
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  4. Sanja Kapitanović
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Corresponding author

Correspondence to Helena Kapitanović Vidak.

Ethics declarations

The study was approved by the Ethics Committee of the Special Hospital for Children with Neurodevelopmental and Motor Difficulties, Goljak 2, Zagreb, Croatia as well as the Ethics Committee of the School of Medicine University of Zagreb and was performed in accordance with the ethical standards of Helsinki Declaration. Written informed consent was obtained from all parents of patients included in the study.

Funding

This study was funded by Ministry of Education, Science and Sports of Croatia (grant number 098-0982464-2508).

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The authors declare that they have no competing interests.

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Kapitanović Vidak, H., Catela Ivković, T., Vidak, Z. et al. COX-1 and COX-2 polymorphisms in susceptibility to cerebral palsy in very preterm infants. Mol Neurobiol 54, 930–938 (2017). https://doi.org/10.1007/s12035-016-9713-9

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  • DOI: https://doi.org/10.1007/s12035-016-9713-9

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