Impaired lipid metabolism markers to assess the risk of neuroinflammation in autism spectrum disorder

  • Hanan Qasem
  • Laila Al-Ayadhi
  • Geir Bjørklund
  • Salvatore Chirumbolo
  • Afaf El-Ansary
Original Article

Abstract

Autism spectrum disorder (ASD) is a multifactorial disorder caused by an interaction between environmental risk factors and a genetic background. It is characterized by impairment in communication, social interaction, repetitive behavior, and sensory processing. The etiology of ASD is still not fully understood, and the role of neuroinflammation in autism behaviors needs to be further investigated. The aim of the present study was to test the possible association between prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), prostaglandin PGE2 EP2 receptors and nuclear kappa B (NF-κB) and the severity of cognitive disorders, social impairment, and sensory dysfunction. PGE2, COX-2, mPGES-1, PGE2-EP2 receptors and NF-κB as biochemical parameters related to neuroinflammation were determined in the plasma of 47 Saudi male patients with ASD, categorized as mild to moderate and severe as indicated by the Childhood Autism Rating Scale (CARS) or the Social Responsiveness Scale (SRS) or the Short Sensory Profile (SSP) and compared to 46 neurotypical controls. The data indicated that ASD patients have remarkably higher levels of the measured parameters compared to neurotypical controls, except for EP2 receptors that showed an opposite trend. While the measured parameter did not correlate with the severity of social and cognitive dysfunction, PGE2, COX-2, and mPGES-1 were remarkably associated with the dysfunction in sensory processing. NF-κB was significantly increased in relation to age. Based on the discussed data, the positive correlation between PGE2, COX-2, and mPGES-1 confirm the role of PGE2 pathway and neuroinflammation in the etiology of ASD, and the possibility of using PGE2, COX-2 and mPGES-1 as biomarkers of autism severity. NF-κB as inflammatory inducer showed an elevated level in plasma of ASD individuals. Receiver operating characteristic analysis together with predictiveness diagrams proved that the measured parameters could be used as predictive biomarkers of biochemical correlates to ASD.

Keywords

Autism Childhood autism rating scale Cyclooxygenase-2, microsomal prostaglandin E synthase-1, neuroinflammation NF-κB: Nuclear factor kappa B, PGE2: prostaglandin E 2, short sensory profile Social responsiveness scale 

Abbreviations

AA

Arachidonic acid

ASD

Autism spectrum disorder

CARS

Childhood autism rating scale

COX-2

Cyclooxygenase-2

cPLA2

Cytosolic phospholipase A2

GSH

Glutathione

IFNγ

Interferon gamma

IL-6

Interleukin-6

mPGES-1

Microsomal prostaglandin E synthase-1

NF-κB

Nuclear factor kappa B

NMDA

N-methyl-D-aspartate

PGE2

Prostaglandin E2

PGE2-EP2

Prostaglandin E2 EP2 receptors

PUFAs

Polyunsaturated fatty acids

ROC-curve

Receiver operating characteristics curve

ROS

Reactive oxygen species

SRS

Social responsiveness scale

SSP

Short sensory profile

TNF-α

Tumor necrosis factor alpha

Notes

Acknowledgements

This research project was supported by a grant from the Research Center of the Center for Female Scientific and Medical Colleges at King Saud University, Riyadh, Saudi Arabia.

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest with respect to the authorship, and/or publication of this article.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

References

  1. Ahmad AS, Zhuang H, Echeverria V, Doré S (2006) Stimulation of prostaglandin EP2 receptors prevents NMDA-induced excitotoxicity. J Neurotrauma 23:1895–1903CrossRefPubMedGoogle Scholar
  2. Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem 42:1032–1040CrossRefPubMedGoogle Scholar
  3. Allan SM, Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc Lond Ser B Biol Sci 358:1669–1677CrossRefGoogle Scholar
  4. Bell JG, MacKinlay EE, Dick JR, MacDonald DJ, Boyle RM, Glen AC (2004) Essential fatty acids and phospholipase A2 in autistic spectrum disorders. Prostaglandins Leukot Essent Fatty Acids 71:201–204CrossRefPubMedGoogle Scholar
  5. Bezzi P, Volterra A (2001) A neuron-glia signalling network in the active brain. Curr Opin Neurobiol 11:387–394CrossRefPubMedGoogle Scholar
  6. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285CrossRefPubMedGoogle Scholar
  7. Bjørklund G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR, Urbina MA (2016) Immune dysfunction and neuroinflammation in autism spectrum disorder. Acta Neurobiol Exp 76:257–268Google Scholar
  8. Blais V, Rivest S (2001) Inhibitory action of nitric oxide on circulating tumor necrosis factor-induced NF-kappaB activity and COX-2 transcription in the endothelium of the brain capillaries. J Neuropathol Exp Neurol 60:893–905CrossRefPubMedGoogle Scholar
  9. Blaylock RL, Strunecka A (2009) Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders. Curr Med Chem 16:157–170CrossRefPubMedGoogle Scholar
  10. Bonventre JV, Huang Z, Taheri MR, O'Leary E, Li E, Moskowitz MA, Sapirstein A (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390:622–625CrossRefPubMedGoogle Scholar
  11. Bradbury J (2011) Docosahexaenoic acid (DHA): an ancient nutrient for the modern human brain. Nutrients 3:529–554CrossRefPubMedPubMedCentralGoogle Scholar
  12. Camacho M, Gerbolés E, Escudero JR, Antón R, García-Moll X, Vila L (2007) Microsomal prostaglandin E synthase-1, which is not coupled to a particular cyclooxygenase isoenzyme, is essential for prostaglandin E(2) biosynthesis in vascular smooth muscle cells. J Thromb Haemost 5:1411–1419CrossRefPubMedGoogle Scholar
  13. Carrasco E, Werner P, Casper D (2008) Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress. Neurosci Lett 441:44–49CrossRefPubMedPubMedCentralGoogle Scholar
  14. Carrero I, Gonzalo MR, Martin B, Sanz-Anquela JM, Arevalo-Serrano J, Gonzalo-Ruiz A (2012) Oligomers of beta-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain. Experimental neurology 236(2): 215–227Google Scholar
  15. Chauhan A, Chauhan V, Brown WT, Cohen I (2004) Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin—the antioxidant proteins. Life Sci 75:2539–2549CrossRefPubMedGoogle Scholar
  16. Chen C, Magee JC, Bazan NG (2002) Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 87:2851–2857CrossRefPubMedGoogle Scholar
  17. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M (2007) Elevation of tumor necrosis factor alpha in CSF of autistic children. Pediatr Neurol 36:361–365CrossRefPubMedGoogle Scholar
  18. Constantino JN, Davis SA, Todd RD, Schindler MK, Gross MM, Brophy SL, Metzger LM, Shoushtari CS, Splinter R, Reich W (2003) Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord 33:427–433CrossRefPubMedGoogle Scholar
  19. Das UN (2013) Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 29:1175–1185CrossRefPubMedGoogle Scholar
  20. Dunn W (1999) Sensory profile manual. Psychological Corporation, San AntonioGoogle Scholar
  21. El-Ansary A, Al-Ayadhi L (2012) Lipid mediators in plasma of autism spectrum disorders. Lipid Health Dis 11:160.  https://doi.org/10.1186/1476-511X-11-160 CrossRefGoogle Scholar
  22. El-Ansary A, Al-Ayadhi L (2014) GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. J Neuroinflammation 11(189):189.  https://doi.org/10.1186/s12974-014-0189-0 CrossRefPubMedPubMedCentralGoogle Scholar
  23. El-Ansary A, Hassan WM, Qasem H, Das UN (2016) Identification of biomarkers of impaired sensory profiles among autistic patients. PLoS One 11:e0164153.  https://doi.org/10.1371/journal.pone.0164153 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Essa MM, Guillemin GJ, Waly MI, Al-Sharbati MM, Al-Farsi YM, Hakkim FL, Ali A, Al-Shafaee MS (2012) Increased markers of oxidative stress in autistic children of the Sultanate of Oman. Biol Trace Elem Res 147:25–27CrossRefPubMedGoogle Scholar
  25. Foudi N, Louedec L, Cachina T, Brink C, Norel X (2009) Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation. Cardiovasc Res 81:269–277CrossRefPubMedGoogle Scholar
  26. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, Bonassi S (2012) Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med 52:2128–2141CrossRefPubMedGoogle Scholar
  27. Frye RE, Delatorre R, Taylor H, Slattery J, Melnyk S, Chowdhury N, James SJ (2013) Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Transl Psychiatry 3:e273.  https://doi.org/10.1038/tp.2013.51 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Gadad BS, Hewitson L, Young KA, German DC (2013) Neuropathology and animal models of autism: genetic and environmental factors. Autism Res Treat 2013:731935–731912.  https://doi.org/10.1155/2013/731935 PubMedPubMedCentralGoogle Scholar
  29. Goines PE, Ashwood P (2013) Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol 36:67–68CrossRefPubMedGoogle Scholar
  30. Gordan J (2013) One in every 50 children has autism. UCLA Medical School CDC. http://www.huffingtonpost.com/jay-gordon/autismrates_b_2921256.html. Accessed 12 October 2017
  31. Hein AM, Stutzman DL, Bland ST, Barrientos RM, Watkins LR, Rudy JW, Maier SF (2007) Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus. Neuroscience 150:754–763CrossRefPubMedPubMedCentralGoogle Scholar
  32. Innis SM (2000) The role of dietary n-6 and n-3 fatty acids in the developing brain. Dev Neurosci 22:474–480CrossRefPubMedGoogle Scholar
  33. Jenab S, Quinones-Jenab V (2002) The effects of interleukin-6, leukemia inhibitory factor and interferon-gamma on STAT DNA binding and c-fos mRNA levels in cortical astrocytes and C6 glioma cells. Neuro Endocrinol Lett 23:325–328PubMedGoogle Scholar
  34. Kaufmann WE, Andreasson KI, Isakson PC, Worley PF (1997) Cyclooxygenases and the central nervous system. Prostaglandins 54:601–624CrossRefPubMedGoogle Scholar
  35. Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12:225–229CrossRefPubMedGoogle Scholar
  36. Kim T, Jae Kim H, Kyung Park J, Woo J, Ho Chung J (2010) Association between polymorphisms of arachidonate 12-lipoxygenase (ALOX12) and schizophrenia in a Korean population. Behav Brain Funct 6:44CrossRefPubMedPubMedCentralGoogle Scholar
  37. King CR (2011) A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: a possible link between twelve autism risk factors and the autism 'epidemic'. Med Hypotheses 76:653–660CrossRefPubMedGoogle Scholar
  38. Kunz T, Oliw EH (2001) The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 13:569–575CrossRefPubMedGoogle Scholar
  39. Kuratko CN, Salem N Jr (2009) Biomarkers of DHA status. Prostaglandins Leukot Essent Fatty Acids 81:111–118CrossRefPubMedGoogle Scholar
  40. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K, Isakson PC, Stallings WC (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648CrossRefPubMedGoogle Scholar
  41. Kwon DJ, Ju SM, Youn GS, Choi SY, Park J (2013) 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 and chemical toxicology 58:479–486Google Scholar
  42. Laflamme N, Lacroix S, Rivest S (1999) An essential role of interleukin-1beta in mediating NF-kappaB activity and COX-2 transcription in cells of the blood-brain barrier in response to a systemic and localized inflammation but not during endotoxemia. J Neurosci 19:10923–10930PubMedGoogle Scholar
  43. Lawrence G (2010) The fats of life: essential fatty acids in health and disease. Rutgers University Press, New BrunswickGoogle Scholar
  44. Lee EO, Shin YJ, Chong YH (2004) Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-alpha: possible involvement of multiple signal transduction and beta-catenin/T-cell factor. J Neuroimmunol 155:21–31CrossRefPubMedGoogle Scholar
  45. Li W, Xia J, Sun GY (1999) Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate. J Interf Cytokine Res 19:121–127CrossRefGoogle Scholar
  46. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116CrossRefPubMedPubMedCentralGoogle Scholar
  47. Liu D, Wu L, Breyer R, Mattson MP, Andreasson K (2005) Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia. Ann Neurol 57:758–761CrossRefPubMedGoogle Scholar
  48. Liu YQ, Hu XY, Lu T, Cheng YN, Young CY, Yuan HQ, Lou HX (2012) Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo. PloS one 7(5):e38000Google Scholar
  49. Lull ME, Block ML (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7:354–365CrossRefPubMedPubMedCentralGoogle Scholar
  50. Manna SK, Zhang HJ, Yan T, Oberley LW, Aggarwal BB (1998) Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of 10.1007/s11011-018-0206-6 nuclear transcription factor-κB and activated protein-1. Journal of Biological Chemistry, 273(21), 13245–13254Google Scholar
  51. Mark KS, Trickler WJ, Miller DW (2001) Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells. J Pharmacol Exp Ther 297:1051–1058PubMedGoogle Scholar
  52. Marshall PJ, Kulmacz RJ, Lands WE (1987) Constraints on prostaglandin biosynthesis in tissues. J Biol Chem 262:3510–3517PubMedGoogle Scholar
  53. Marusic S, Leach MW, Pelker JW, Azoitei ML, Uozumi N, Cui J, Shen MW, DeClercq CM, Miyashiro JS, Carito BA, Thakker P, Simmons DL, Leonard JP, Shimizu T, Clark JD (2005) Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis. J Exp Med 202:841–851CrossRefPubMedPubMedCentralGoogle Scholar
  54. McCullough L, Wu L, Haughey N, Liang X, Hand T, Wang Q, Breyer RM, Andreasson K (2004) Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. J Neurosci 24:257–268CrossRefPubMedGoogle Scholar
  55. Meguid NA, Dardir AA, Abdel-Raouf ER, Hashish A (2011) Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation. Biol Trace Elem Res 143:58–65CrossRefPubMedGoogle Scholar
  56. Mick K (2005) Diagnosing autism: comparison of the childhood autism rating scale (CARS) and the autism diagnostic observation schedule (ADOS). Dissertation, Wichita State UniversityGoogle Scholar
  57. Moolwaney AS, Igwe OJ (2005) Regulation of the cyclooxygenase-2 system by interleukin-1beta through mitogen-activated protein kinase signaling pathways: a comparative study of human neuroglioma and neuroblastoma cells. Brain Res Mol Brain Res 137:202–212CrossRefPubMedGoogle Scholar
  58. Naik US, Gangadharan C, Abbagani K, Nagalla B, Dasari N, Manna SK (2011) A study of nuclear transcription factor-kappa B in childhood autism. PLoS One 6:e19488.  https://doi.org/10.1371/journal.pone.0019488 CrossRefPubMedPubMedCentralGoogle Scholar
  59. O'Banion MK, Miller JC, Chang JW, Kaplan MD, Coleman PD (1996) Interleukin-1 beta induces prostaglandin G/H synthase-2 (cyclooxygenase-2) in primary murine astrocyte cultures. J Neurochem 66:2532–2540CrossRefPubMedGoogle Scholar
  60. Pooler AM, Arjona AA, Lee RK, Wurtman RJ (2004) Prostaglandin E2 regulates amyloid precursor protein expression via the EP2 receptor in cultured rat microglia. Neurosci Lett 362:127–130CrossRefPubMedGoogle Scholar
  61. Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW (1998) Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav Immun 12:212–229CrossRefPubMedGoogle Scholar
  62. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364CrossRefPubMedGoogle Scholar
  63. Richardson AJ (2004) Long-chain polyunsaturated fatty acids in childhood developmental and psychiatric disorders. Lipids 39:1215–1222CrossRefPubMedGoogle Scholar
  64. Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry 2:e134.  https://doi.org/10.1038/tp.2012.61 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Rossignol DA, Frye RE (2012) A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 17:389–401CrossRefPubMedGoogle Scholar
  66. Rossignol DA, Frye RE (2014) Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism. Front Physiol 5(150).  https://doi.org/10.3389/fphys.2014.00150
  67. Samuelsson B, Morgenstern R, Jakobsson PJ (2007) Membrane prostaglandin E synthase-1: a novel therapeutic target. Pharmacol Rev 59:207–224CrossRefPubMedGoogle Scholar
  68. Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C (2005) Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci 25:9858–9870CrossRefPubMedGoogle Scholar
  69. Sareddy GR, Geeviman K, Ramulu C, Babu PP (2012) The nonsteroidal anti-inflammatory drug celecoxib suppresses the growth and induces apoptosis of human glioblastoma cells via the NF-κB pathway. J Neuro-Oncol 106:99–109CrossRefGoogle Scholar
  70. Savonenko A, Munoz P, Melnikova T, Wang Q, Liang X, Breyer RM, Montine TJ, Kirkwood A, Andreasson K (2009) Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor. Exp Neurol 217:63–73CrossRefPubMedPubMedCentralGoogle Scholar
  71. Schuchardt JP, Huss M, Stauss-Grabo M, Hahn A (2010) Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr 169:149–164CrossRefPubMedGoogle Scholar
  72. Silver WG, Rapin I (2012) Neurobiological basis of autism. Pediatr Clin N Am 59:45–61CrossRefGoogle Scholar
  73. Simmons DL, Botting RM, Hla T (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387–437CrossRefPubMedGoogle Scholar
  74. Song C, Horrobin D (2004) Omega-3 fatty acid ethyl -eicosapentaenoate, but not soybean oil, attenuates memory impairment induced by central IL-1 beta administration. J Lipid Res 45:1112–1121CrossRefPubMedGoogle Scholar
  75. Sun Q, Ma J, Campos H, Hankinson SE, Hu FB (2007) Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. Am J Clin Nutr 86:74–81CrossRefPubMedGoogle Scholar
  76. Swiergiel AH, Dunn AJ (2002) Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. J Pharmacol Exp Ther 302:1031–1036CrossRefPubMedGoogle Scholar
  77. Tammali R, Ramana KV, Srivastava SK (2007) Aldose reductase regulates TNF-alpha-induced PGE2 production in human colon cancer cells. Cancer Lett 252:299–306CrossRefPubMedPubMedCentralGoogle Scholar
  78. Tassoni D, Kaur G, Weisinger RS, Sinclair AJ (2008) The role of eicosanoids in the brain. Asia Pac J Clin Nutr 17(Suppl 1):220–228PubMedGoogle Scholar
  79. Tian J, Kim SF, Hester L, Snyder SH (2008) S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity. Proc Natl Acad Sci U S A 105:10537–10540CrossRefPubMedPubMedCentralGoogle Scholar
  80. Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y, Miyazaki J, Shimizu T (1997) Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390:618–622CrossRefPubMedGoogle Scholar
  81. Uracz W, Uracz D, Olszanecki R, Gryglewski RJ (2002) Interleukin 1beta induces functional prostaglandin E synthase in cultured human umbilical vein endothelial cells. J Physiol Pharmacol 53:643–654PubMedGoogle Scholar
  82. Vancassel S, Durand G, Barthélémy C, Lejeune B, Martineau J, Guilloteau D, Andrès C, Chalon S (2001) Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 65:1–7CrossRefPubMedGoogle Scholar
  83. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81CrossRefPubMedGoogle Scholar
  84. Verhoeven JS, De Cock P, Lagae L, Sunaert S (2010) Neuroimaging of autism. Neuroradiology 52:3–14CrossRefPubMedGoogle Scholar
  85. Vila L (2004) Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis. Med Res Rev 24:399–424CrossRefPubMedGoogle Scholar
  86. Wallace JL (2001) Prostaglandin biology in inflammatory bowel disease. Gastroenterol Clin N Am 30:971–980CrossRefGoogle Scholar
  87. Wang F, Wu H, Xu S, Guo X, Yang J, Shen X (2011) Macrophage migration inhibitory factor activates cyclooxygenase 2-prostaglandin E2 in cultured spinal microglia. Neurosci Res 71:210–218CrossRefPubMedGoogle Scholar
  88. Warner TD, Vojnovic I, Giuliano F, Jiménez R, Bishop-Bailey D, Mitchell JA (2004) Cyclooxygenases 1, 2, and 3 and the production of prostaglandin I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues. J Pharmacol Exp Ther 310:642–647CrossRefPubMedGoogle Scholar
  89. World Medical Association (2000) World Medical Association declaration of Helsinki: ethical principles for medical research involving human subjects. Edinburgh, Canary PublicationsGoogle Scholar
  90. Xu J, Yu S, Sun AY, Sun GY (2003) Oxidant-mediated AA release from astrocytes involves cPLA(2) and iPLA(2). Free Radic Biol Med 34:1531–1543CrossRefPubMedGoogle Scholar
  91. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–786CrossRefPubMedGoogle Scholar
  92. Yang H, Zhang J, Breyer RM, Chen C (2009) Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor. J Neurochem 108:295–304CrossRefPubMedGoogle Scholar
  93. Yoo HJ, Kim H-W, Cho IH, Kim SA, Park M, Kim JW (2008) Are the behavioural phenotypes different according to the genotype of iNOS and COX-2 genes in autism spectrum disorders? Int. J. Devl. Neuroscience 26:867–892Google Scholar
  94. Zonta M, Sebelin A, Gobbo S, Fellin T, Pozzan T, Carmignoto G (2003) Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J Physiol 553:407–414CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hanan Qasem
    • 1
  • Laila Al-Ayadhi
    • 2
    • 3
    • 4
  • Geir Bjørklund
    • 5
  • Salvatore Chirumbolo
    • 6
  • Afaf El-Ansary
    • 2
    • 3
    • 7
    • 8
  1. 1.Biochemistry Department, Science CollegeKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Autism Research and Treatment CenterRiyadhSaudi Arabia
  3. 3.Shaik AL-Amodi Autism Research ChairKing Saud UniversityRiyadhSaudi Arabia
  4. 4.Physiology Department, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  5. 5.Council for Nutritional and Environmental MedicineMo i RanaNorway
  6. 6.Department of Neurological and Movement SciencesUniversity of VeronaVeronaItaly
  7. 7.Central laboratory, Female Centre for Scientific and Medical StudiesKing Saud UniversityRiyadhSaudi Arabia
  8. 8.Therapeutic Chemistry DepartmentNational Research CenterGuizaEgypt

Personalised recommendations