Skip to main content

Advertisement

SpringerLink
Log in

Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2α, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2α, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca2+ homeostasis by impairing Na+-Ca2+ exchange via EP1, resulting in the excess Ca2+ accumulation. Neither PGE2, PGF2α, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Δ12,14-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AA:

Arachidonic acid

Aβ:

Amyloid β protein

AC:

Adenylate cyclase

AD:

Alzheimer’s disease

AIDS:

Acquired immunodeficiency syndrome

ALS:

Amyotrophic lateral sclerosis

AMPA:

Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BD:

Bipolar disorder

CaMK II:

Calcium/calmodulin-dependent protein kinase II

CJD:

Creutzfeldt-Jakob disease

CNS:

Central nervous system

COX:

Cyclooxygenase

CRTH2:

Chemoattractant receptor homologous molecule expressed on Th2 cells

CSF:

Cerebrospinal fluid

cPGES:

Cytosolic PGE synthase

cPLA2 :

Cytosolic phospholipase A2

15d-PGJ2 :

15-deoxy-Δ12,14-PGJ2

DP:

Receptors for PGD2

EP:

Receptors for PGE2

ER:

Endoplasmic reticulum

FP:

Receptors for PGF2α

H-PGDS:

Hematopoietic PGD synthase

6-OHDA:

6-Hydroxydopamine

IP:

Receptors for PGI2

L-VDCC:

L-type voltage-dependent calcium channel

L-PGDS:

Lipocalin-type PGD synthase

LTP:

Long-term potentiation

L-VDCC:

L-type voltage-dependent Ca2+ channel

MAPK:

Mitogen-activated protein kinase

MCA:

Middle cerebral artery

mPGES:

Membrane-associated perinuclear PGE synthase

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS:

Multiple sclerosis

NMDA:

N-methyl-d-aspartate

NSAIDs:

Nonsteroidal anti-inflammatory drugs

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS:

Multiple sclerosis

PD:

Parkinson’s disease

PG:

Prostaglandin

PPARγ:

Peroxysome proliferators-activated receptor γ

PLA2 :

Phospholipase A2

PLC:

Phospholipase C

PKC:

Calcium-dependent protein kinase

PKA:

cAMP-dependent protein kinase

sPLA2 :

Secreted phospholipase A2

SNpc:

Substantia nigra pars compacta

TP:

Receptors for TXA2

TXA2 :

Thromboxane A2

WT:

Wild type

References

  1. Feng L, Sun W, Xia Y, Tang WW, Chanmugam P, Soyoola E, Wilson CB, Hwang D (1993) Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression. Arch Biochem Biophys 307(2):361–368

    Article  CAS  PubMed  Google Scholar 

  2. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 99(21):13926–13931. doi:10.1073/pnas.162468699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Deininger MH, Schluesener HJ (1999) Cyclooxygenases-1 and -2 are differentially localized to microglia and endothelium in rat EAE and glioma. J Neuroimmunol 95(1–2):202–208

    Article  CAS  PubMed  Google Scholar 

  4. 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(2):371–386

    Article  CAS  PubMed  Google Scholar 

  5. Kaufmann WE, Worley PF, Pegg J, Bremer M, Isakson P (1996) COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc Natl Acad Sci U S A 93(6):2317–2321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yagami T (2006) Cerebral arachidonate cascade in dementia: Alzheimer’s disease and vascular dementia. Curr Neuropharmacol 4(1):87–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Niwa K, Araki E, Morham SG, Ross ME, Iadecola C (2000) Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci Off J Soc Neurosci 20(2):763–770

    CAS  Google Scholar 

  8. Yagami T, Yamamoto Y, Koma H (2014) The role of secretory phospholipase A(2) in the central nervous system and neurological diseases. Mol Neurobiol 49(2):863–876. doi:10.1007/s12035-013-8565-9

    Article  CAS  PubMed  Google Scholar 

  9. Malinow R, Schulman H, Tsien RW (1989) Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245(4920):862–866

    Article  CAS  PubMed  Google Scholar 

  10. English JD, Sweatt JD (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J Biol Chem 272(31):19103–19106

    Article  CAS  PubMed  Google Scholar 

  11. Chen C, Magee JC, Bazan NG (2002) Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 87(6):2851–2857

    CAS  PubMed  Google Scholar 

  12. Berrouschot J, Sterker M, Bettin S, Koster J, Schneider D (1998) Mortality of space-occupying (‘malignant’) middle cerebral artery infarction under conservative intensive care. Intensive Care Med 24 (6):620–623

  13. Sacco S, Marini C, Toni D, Olivieri L, Carolei A (2009) Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke; a journal of cerebral circulation 40(2):394–399. doi:10.1161/STROKEAHA.108.523209

  14. Shmelzer Z, Haddad N, Admon E, Pessach I, Leto TL, Eitan-Hazan Z, Hershfinkel M, Levy R (2003) Unique targeting of cytosolic phospholipase A2 to plasma membranes mediated by the NADPH oxidase in phagocytes. J Cell Biol 162(4):683–692. doi:10.1083/jcb.200211056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shmelzer Z, Karter M, Eisenstein M, Leto TL, Hadad N, Ben-Menahem D, Gitler D, Banani S et al (2008) Cytosolic phospholipase A2alpha is targeted to the p47phox-PX domain of the assembled NADPH oxidase via a novel binding site in its C2 domain. J Biol Chem 283(46):31898–31908. doi:10.1074/jbc.M804674200

    Article  CAS  PubMed  Google Scholar 

  16. Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac’h-Pillot K, Koziel V, Yen-Potin FT, Bihain B et al (2005) Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-beta peptide. FASEB J 19(1):85–87. doi:10.1096/fj.04-1807fje

    CAS  PubMed  Google Scholar 

  17. Malaplate-Armand C, Florent-Bechard S, Youssef I, Koziel V, Sponne I, Kriem B, Leininger-Muller B, Olivier JL et al (2006) Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 23(1):178–189. doi:10.1016/j.nbd.2006.02.010

    Article  CAS  PubMed  Google Scholar 

  18. He X, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31(3):398–408. doi:10.1016/j.neurobiolaging.2008.05.010

    Article  CAS  PubMed  Google Scholar 

  19. Casals JB, Pieri NC, Feitosa ML, Ercolin AC, Roballo KC, Barreto RS, Bressan FF, Martins DS et al (2011) The use of animal models for stroke research: a review. Comp Med 61(4):305–313

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rossmeisl JH, Jr., Rohleder JJ, Pickett JP, Duncan R, Herring IP (2007) Presumed and confirmed striatocapsular brain infarctions in six dogs. Vet Ophthalmol 10(1):23–36. doi:10.1111/j.1463-5224.2007.00487.x

  21. Umemura K, Nakashima M (1993) A new model of middle cerebral artery thrombosis in rats. Yakubutsu Seishin Kodo = Jpn J Psychiatr Treat 13(1):9–17

    CAS  Google Scholar 

  22. Sairanen T, Ristimaki A, Karjalainen-Lindsberg ML, Paetau A, Kaste M, Lindsberg PJ (1998) Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol 43(6):738–747. doi:10.1002/ana.410430608

    Article  CAS  PubMed  Google Scholar 

  23. Nogawa S, Zhang F, Ross ME, Iadecola C (1997) Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci Off J Soc Neurosci 17(8):2746–2755

    CAS  Google Scholar 

  24. Yagami T, Ueda K, Asakura K, Hata S, Kuroda T, Sakaeda T, Takasu N, Tanaka K et al (2002) Human group IIA secretory phospholipase A2 induces neuronal cell death via apoptosis. Mol Pharmacol 61(1):114–126

    Article  CAS  PubMed  Google Scholar 

  25. Yagami T, Ueda K, Asakura K, Hayasaki-Kajiwara Y, Nakazato H, Sakaeda T, Hata S, Kuroda T et al (2002) Group IB secretory phospholipase A2 induces neuronal cell death via apoptosis. J Neurochem 81(3):449–461

    Article  CAS  PubMed  Google Scholar 

  26. Yagami T, Ueda K, Asakura K, Hata S, Kuroda T, Sakaeda T, Kishino J, Sakaguchi G et al (2002) Group IB secretory phospholipase A(2)induces cell death in the cultured cortical neurons: a possible involvement of its binding sites. Brain Res 949(1–2):197–201

    Article  CAS  PubMed  Google Scholar 

  27. Lin TN, Wang Q, Simonyi A, Chen JJ, Cheung WM, He YY, Xu J, Sun AY et al (2004) Induction of secretory phospholipase A2 in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain. J Neurochem 90(3):637–645

    Article  CAS  PubMed  Google Scholar 

  28. Yagami T, Ueda K, Asakura K, Sakaeda T, Hata S, Kuroda T, Sakaguchi G, Itoh N et al (2003) Porcine pancreatic group IB secretory phospholipase A2 potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels. Brain Res 960(1–2):71–80

    Article  CAS  PubMed  Google Scholar 

  29. Yagami T, Ueda K, Asakura K, Nakazato H, Hata S, Kuroda T, Sakaeda T, Sakaguchi G et al (2003) Human group IIA secretory phospholipase A2 potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels in cultured rat cortical neurons. J Neurochem 85(3):749–758

    Article  CAS  PubMed  Google Scholar 

  30. Niwa K, Haensel C, Ross ME, Iadecola C (2001) Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res 88(6):600–608

    Article  CAS  PubMed  Google Scholar 

  31. Iadecola C, Sugimoto K, Niwa K, Kazama K, Ross ME (2001) Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 21(12):1436–1441. doi:10.1097/00004647-200112000-00008

    Article  CAS  Google Scholar 

  32. Li W, Wu S, Hickey RW, Rose ME, Chen J, Graham SH (2008) Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture. Neurochem Res 33(3):490–499

  33. Tomimoto H, Shibata M, Ihara M, Akiguchi I, Ohtani R, Budka H (2002) A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during cerebral ischemia in humans. Acta Neuropathol 104(6):601–607. doi:10.1007/s00401-002-0590-0

    CAS  PubMed  Google Scholar 

  34. Yagami T, Ueda K, Hata S, Kuroda T, Itoh N, Sakaguchi G, Okamura N, Sakaeda T et al (2005) S-2474, a novel nonsteroidal anti-inflammatory drug, rescues cortical neurons from human group IIA secretory phospholipase A(2)-induced apoptosis. Neuropharmacology 49(2):174–184. doi:10.1016/j.neuropharm.2005.02.011

    Article  CAS  PubMed  Google Scholar 

  35. Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6(4):487–498

    Article  CAS  PubMed  Google Scholar 

  36. Ueda K, Shinohara S, Yagami T, Asakura K, Kawasaki K (1997) Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals. J Neurochem 68(1):265–271

    Article  CAS  PubMed  Google Scholar 

  37. Ueda K, Yagami T, Kageyama H, Kawasaki K (1996) Protein kinase inhibitor attenuates apoptotic cell death induced by amyloid beta protein in culture of the rat cerebral cortex. Neurosci Lett 203(3):175–178

    Article  CAS  PubMed  Google Scholar 

  38. Yermakova AV, Rollins J, Callahan LM, Rogers J, O’Banion MK (1999) Cyclooxygenase-1 in human Alzheimer and control brain: quantitative analysis of expression by microglia and CA3 hippocampal neurons. J Neuropathol Exp Neurol 58(11):1135–1146

    Article  CAS  PubMed  Google Scholar 

  39. Pasinetti GM, Aisen PS (1998) Cyclooxygenase-2 expression is increased in frontal cortex of Alzheimer’s disease brain. Neuroscience 87(2):319–324

    Article  CAS  PubMed  Google Scholar 

  40. Hwang DY, Chae KR, Kang TS, Hwang JH, Lim CH, Kang HK, Goo JS, Lee MR et al (2002) Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease. FASEB J 16(8):805–813. doi:10.1096/fj.01-0732com

    Article  CAS  PubMed  Google Scholar 

  41. Cui JG, Kuroda H, Chandrasekharan NV, Pelaez RP, Simmons DL, Bazan NG, Lukiw WJ (2004) Cyclooxygenase-3 gene expression in Alzheimer hippocampus and in stressed human neural cells. Neurochem Res 29(9):1731–1737

    Article  CAS  PubMed  Google Scholar 

  42. Launer L (2003) Nonsteroidal anti-inflammatory drug use and the risk for Alzheimer’s disease: dissecting the epidemiological evidence. Drugs 63(8):731–739

    Article  PubMed  Google Scholar 

  43. Rogers J, Kirby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Cofield M et al (1993) Clinical trial of indomethacin in Alzheimer’s disease. Neurology 43(8):1609–1611

    Article  CAS  PubMed  Google Scholar 

  44. Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, Trojanowski JQ, Lee VM et al (2004) Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer’s disease. Am J Pathol 165(6):2197–2206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Szekely CA, Green RC, Breitner JC, Ostbye T, Beiser AS, Corrada MM, Dodge HH, Ganguli M et al (2008) No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. Neurology 70(24):2291–2298. doi:10.1212/01.wnl.0000313933.17796.f6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yagami T, Ueda K, Asakura K, Sakaeda T, Kuroda T, Hata S, Kambayashi Y, Fujimoto M (2001) Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid beta protein-induced neuronal cell death. Br J Pharmacol 134(3):673–681. doi:10.1038/sj.bjp.0704261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Teismann P (2012) COX-2 in the neurodegenerative process of Parkinson’s disease. Biofactors 38(6):395–397. doi:10.1002/biof.1035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V et al (2003) Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci U S A 100(9):5473–5478. doi:10.1073/pnas.0837397100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Teismann P, Ferger B (2001) Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson’s disease. Synapse 39(2):167–174. doi:10.1002/1098-2396(200102)39:2<167::AID-SYN8>3.0.CO;2-U

    Article  CAS  PubMed  Google Scholar 

  50. Feng ZH, Wang TG, Li DD, Fung P, Wilson BC, Liu B, Ali SF, Langenbach R et al (2002) Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329(3):354–358

    Article  CAS  PubMed  Google Scholar 

  51. Prat A, Antel J (2005) Pathogenesis of multiple sclerosis. Curr Opin Neurol 18(3):225–230

    Article  CAS  PubMed  Google Scholar 

  52. Rose JW, Hill KE, Watt HE, Carlson NG (2004) Inflammatory cell expression of cyclooxygenase-2 in the multiple sclerosis lesion. J Neuroimmunol 149(1–2):40–49. doi:10.1016/j.jneuroim.2003.12.021

    Article  CAS  PubMed  Google Scholar 

  53. Carlson NG, Hill KE, Tsunoda I, Fujinami RS, Rose JW (2006) The pathologic role for COX-2 in apoptotic oligodendrocytes in virus induced demyelinating disease: implications for multiple sclerosis. J Neuroimmunol 174(1–2):21–31. doi:10.1016/j.jneuroim.2006.01.008

    Article  CAS  PubMed  Google Scholar 

  54. Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F (2012) The cyclooxygenase-2 pathway via the PGE(2) EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. J Neurochem 121(3):418–427. doi:10.1111/j.1471-4159.2011.07363.x

    Article  CAS  PubMed  Google Scholar 

  55. Liang X, Wu L, Wang Q, Hand T, Bilak M, McCullough L, Andreasson K (2007) Function of COX-2 and prostaglandins in neurological disease. J Mol Neurosci 33(1):94–99

    Article  CAS  PubMed  Google Scholar 

  56. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P (2006) COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol 6:12. doi:10.1186/1471-2377-6-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Yasojima K, Tourtellotte WW, McGeer EG, McGeer PL (2001) Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy. Neurology 57(6):952–956

    Article  CAS  PubMed  Google Scholar 

  58. Almer G, Guegan C, Teismann P, Naini A, Rosoklija G, Hays AP, Chen C, Przedborski S (2001) Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol 49(2):176–185

    Article  CAS  PubMed  Google Scholar 

  59. Drachman DB, Frank K, Dykes-Hoberg M, Teismann P, Almer G, Przedborski S, Rothstein JD (2002) Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol 52(6):771–778. doi:10.1002/ana.10374

    Article  CAS  PubMed  Google Scholar 

  60. Sharma AK, Reams RY, Jordan WH, Miller MA, Thacker HL, Snyder PW (2007) Mesial temporal lobe epilepsy: pathogenesis, induced rodent models and lesions. Toxicol Pathol 35(7):984–999. doi:10.1080/01926230701748305

    Article  PubMed  Google Scholar 

  61. Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the epileptic brain. Neuron 58(2):168–178. doi:10.1016/j.neuron.2008.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Desjardins P, Sauvageau A, Bouthillier A, Navarro D, Hazell AS, Rose C, Butterworth RF (2003) Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem Int 42(4):299–303

    Article  CAS  PubMed  Google Scholar 

  63. Kunz T, Oliw EH (2001) Nimesulide aggravates kainic acid-induced seizures in the rat. Pharmacol Toxicol 88(5):271–276

    Article  CAS  PubMed  Google Scholar 

  64. Silakova JM, Hewett JA, Hewett SJ (2004) Naproxen reduces excitotoxic neurodegeneration in vivo with an extended therapeutic window. J Pharmacol Exp Ther 309(3):1060–1066. doi:10.1124/jpet.103.063867

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Gobbo OL, O’Mara SM (2004) Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration. Neuroscience 125(2):317–327. doi:10.1016/j.neuroscience.2004.01.045

    Article  CAS  PubMed  Google Scholar 

  67. Takemiya T, Suzuki K, Sugiura H, Yasuda S, Yamagata K, Kawakami Y, Maru E (2003) Inducible brain COX-2 facilitates the recurrence of hippocampal seizures in mouse rapid kindling. Prostaglandins Other Lipid Mediat 71(3–4):205–216

    Article  CAS  PubMed  Google Scholar 

  68. Manabe Y, Anrather J, Kawano T, Niwa K, Zhou P, Ross ME, Iadecola C (2004) Prostanoids, not reactive oxygen species, mediate COX-2-dependent neurotoxicity. Ann Neurol 55(5):668–675. doi:10.1002/ana.20078

    Article  CAS  PubMed  Google Scholar 

  69. Schultz SK, Andreasen NC (1999) Schizophrenia. Lancet 353(9162):1425–1430

    Article  CAS  PubMed  Google Scholar 

  70. Wei J, Hemmings GP (2004) A study of a genetic association between the PTGS2/PLA2G4A locus and schizophrenia. Prostaglandins Leukot Essent Fat Acids 70(4):413–415. doi:10.1016/j.plefa.2003.12.018

    Article  CAS  Google Scholar 

  71. Rao JS, Kim HW, Harry GJ, Rapoport SI, Reese EA (2013) Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr Res 147(1):24–31. doi:10.1016/j.schres.2013.02.017

    Article  PubMed  Google Scholar 

  72. Muller N, Myint AM, Krause D, Weidinger E, Schwarz MJ (2013) Anti-inflammatory treatment in schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 42:146–153. doi:10.1016/j.pnpbp.2012.11.008

    Article  CAS  Google Scholar 

  73. Sommer IE, de Witte L, Begemann M, Kahn RS (2012) Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry 73(4):414–419. doi:10.4088/JCP.10r06823

    Article  CAS  PubMed  Google Scholar 

  74. Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, Correll CU (2013) Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull 39(6):1230–1241. doi:10.1093/schbul/sbt070

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kim HW, Rapoport SI, Rao JS (2011) Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol Psychiatry 16(4):419–428

  76. Ketterer MW, Brymer J, Rhoads K, Kraft P, Lovallo WR (1996) Is aspirin, as used for antithrombosis, an emotion-modulating agent? J Psychosom Res 40(1):53–58

    Article  CAS  PubMed  Google Scholar 

  77. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23(2):87–94. doi:10.1002/hup.912

    Article  CAS  PubMed  Google Scholar 

  78. Rapoport SI (2014) Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem Neurosci 5(6):459–467. doi:10.1021/cn500058v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Deininger MH, Bekure-Nemariam K, Trautmann K, Morgalla M, Meyermann R, Schluesener HJ (2003) Cyclooxygenase-1 and −2 in brains of patients who died with sporadic Creutzfeldt-Jakob disease. J Mol Neurosci 20(1):25–30. doi:10.1385/JMN:20:1:25

    Article  CAS  PubMed  Google Scholar 

  80. Minghetti L, Pocchiari M (2007) Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases. Int Rev Neurobiol 82:265–275. doi:10.1016/S0074-7742(07)82014-9

    Article  CAS  PubMed  Google Scholar 

  81. Griffin DE, Wesselingh SL, McArthur JC (1994) Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol 35(5):592–597. doi:10.1002/ana.410350513

    Article  CAS  PubMed  Google Scholar 

  82. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro-Oncology 4(4):278–299

    PubMed  PubMed Central  Google Scholar 

  83. Deininger MH, Meyermann R, Trautmann K, Morgalla M, Duffner F, Grote EH, Wickboldt J, Schluesener HJ (2000) Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression. Brain Res 885(1):111–116

    Article  CAS  PubMed  Google Scholar 

  84. Joki T, Heese O, Nikas DC, Bello L, Zhang J, Kraeft SK, Seyfried NT, Abe T et al (2000) Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398. Cancer Res 60(17):4926–4931

    CAS  PubMed  Google Scholar 

  85. Kang HC, Kim IH, Park CI, Park SH (2014) Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy. Neuropathol Off J Jpn Soc Neuropathol 34(5):446–454. doi:10.1111/neup.12128

    Article  CAS  Google Scholar 

  86. Mitchell JA, Warner TD (1999) Cyclo-oxygenase-2: pharmacology, physiology, biochemistry and relevance to NSAID therapy. Br J Pharmacol 128(6):1121–1132. doi:10.1038/sj.bjp.0702897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Murakami M, Kambe T, Shimbara S, Kudo I (1999) Functional coupling between various phospholipase A2s and cyclooxygenases in immediate and delayed prostanoid biosynthetic pathways. J Biol Chem 274(5):3103–3115

    Article  CAS  PubMed  Google Scholar 

  88. Ohno K, Fujiwara M, Fukushima M, Narumiya S (1986) Metabolic dehydration of prostaglandin E2 and cellular uptake of the dehydration product: correlation with prostaglandin E2-induced growth inhibition. Biochem Biophys Res Commun 139(2):808–815

    Article  CAS  PubMed  Google Scholar 

  89. Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I (2000) Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis. J Biol Chem 275(42):32775–32782. doi:10.1074/jbc.M003504200

    Article  CAS  PubMed  Google Scholar 

  90. Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M et al (2000) Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem 275(42):32783–32792. doi:10.1074/jbc.M003505200

    Article  CAS  PubMed  Google Scholar 

  91. Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K et al (2003) Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J Biol Chem 278(39):37937–37947. doi:10.1074/jbc.M305108200

    Article  CAS  PubMed  Google Scholar 

  92. Vazquez-Tello A, Fan L, Hou X, Joyal JS, Mancini JA, Quiniou C, Clyman RI, Gobeil F Jr et al (2004) Intracellular-specific colocalization of prostaglandin E2 synthases and cyclooxygenases in the brain. Am J Physiol Regul Integr Comp Physiol 287(5):R1155–R1163. doi:10.1152/ajpregu.00077.2004

    Article  CAS  PubMed  Google Scholar 

  93. 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 Off J Soc Neurosci 25(43):9858–9870. doi:10.1523/JNEUROSCI.2392-05.2005

    Article  CAS  Google Scholar 

  94. Ikeda-Matsuo Y, Hirayama Y, Ota A, Uematsu S, Akira S, Sasaki Y (2010) Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity. Br J Pharmacol 159(5):1174–1186. doi:10.1111/j.1476-5381.2009.00595.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chaudhry UA, Zhuang H, Crain BJ, Dore S (2008) Elevated microsomal prostaglandin-E synthase-1 in Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 4(1):6–13. doi:10.1016/j.jalz.2007.10.015

    Article  CAS  Google Scholar 

  96. Zhu P, Genc A, Zhang X, Zhang J, Bazan NG, Chen C (2005) Heterogeneous expression and regulation of hippocampal prostaglandin E2 receptors. J Neurosci Res 81(6):817–826. doi:10.1002/jnr.20597

    Article  CAS  PubMed  Google Scholar 

  97. Akaneya Y, Tsumoto T (2006) Bidirectional trafficking of prostaglandin E2 receptors involved in long-term potentiation in visual cortex. J Neurosci Off J Soc Neurosci 26(40):10209–10221. doi:10.1523/JNEUROSCI.3028-06.2006

    Article  CAS  Google Scholar 

  98. Yokota C, Kaji T, Kuge Y, Inoue H, Tamaki N, Minematsu K (2004) Temporal and topographic profiles of cyclooxygenase-2 expression during 24 h of focal brain ishemia in rats. Neurosci Lett 357(3):219–222. doi:10.1016/j.neulet.2003.12.109

    Article  CAS  PubMed  Google Scholar 

  99. Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S et al (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12(2):225–229. doi:10.1038/nm1362

    Article  CAS  PubMed  Google Scholar 

  100. Akaike A, Kaneko S, Tamura Y, Nakata N, Shiomi H, Ushikubi F, Narumiya S (1994) Prostaglandin E2 protects cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res 663(2):237–243

    Article  CAS  PubMed  Google Scholar 

  101. Hell JW, Yokoyama CT, Wong ST, Warner C, Snutch TP, Catterall WA (1993) Differential phosphorylation of two size forms of the neuronal class C L-type calcium channel alpha 1 subunit. J Biol Chem 268(26):19451–19457

    CAS  PubMed  Google Scholar 

  102. Yagami T, Ueda K, Asakura K, Takasu N, Sakaeda T, Itoh N, Sakaguchi G, Kishino J, Nakazato H, Katsuyama Y, Nagasaki T, Okamura N, Hori Y, Hanasaki K, Arimura A, Fujimoto M (2003) Novel binding sites of 15-deoxy-Delta12,14-prostaglandin J2 in plasma membranes from primary rat cortical neurons. Exp Cell Res 291(1):212–227

  103. 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 Off J Soc Neurosci 24(1):257–268. doi:10.1523/JNEUROSCI.4485-03.2004

    Article  CAS  Google Scholar 

  104. Liang X, Lin L, Woodling NS, Wang Q, Anacker C, Pan T, Merchant M, Andreasson K (2011) Signaling via the prostaglandin E(2) receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest 121(11):4362–4371. doi:10.1172/JCI46279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ahmad M, Ahmad AS, Zhuang H, Maruyama T, Narumiya S, Dore S (2007) Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury. J Neuroimmunol 184(1–2):172–179. doi:10.1016/j.jneuroim.2006.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Montine TJ, Sidell KR, Crews BC, Markesbery WR, Marnett LJ, Roberts LJ 2nd, Morrow JD (1999) Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 53(7):1495–1498

    Article  CAS  PubMed  Google Scholar 

  107. Wong PT, McGeer PL, McGeer EG (1992) Decreased prostaglandin synthesis in postmortem cerebral cortex from patients with Alzheimer’s disease. Neurochem Int 21(2):197–202

    Article  CAS  PubMed  Google Scholar 

  108. Akitake Y, Nakatani Y, Kamei D, Hosokawa M, Akatsu H, Uematsu S, Akira S, Kudo I et al (2013) Microsomal prostaglandin E synthase-1 is induced in Alzheimer’s disease and its deletion mitigates Alzheimer’s disease-like pathology in a mouse model. J Neurosci Res 91(7):909–919. doi:10.1002/jnr.23217

    Article  CAS  PubMed  Google Scholar 

  109. Forloni G, Chiesa R, Smiroldo S, Verga L, Salmona M, Tagliavini F, Angeretti N (1993) Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35. Neuroreport 4(5):523–526

    Article  CAS  PubMed  Google Scholar 

  110. Yagami T, Nakazato H, Ueda K, Asakura K, Kuroda T, Hata S, Sakaeda T, Sakaguchi G et al (2003) Prostaglandin E2 rescues cortical neurons from amyloid beta protein-induced apoptosis. Brain Res 959(2):328–335

    Article  CAS  PubMed  Google Scholar 

  111. Echeverria V, Clerman A, Dore S (2005) Stimulation of PGE receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following beta-amyloid exposure. Eur J Neurosci 22(9):2199–2206. doi:10.1111/j.1460-9568.2005.04427.x

    Article  PubMed  Google Scholar 

  112. Shie FS, Breyer RM, Montine TJ (2005) Microglia lacking E prostanoid receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity. Am J Pathol 166(4):1163–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhen G, Kim YT, Li RC, Yocum J, Kapoor N, Langer J, Dobrowolski P, Maruyama T et al (2012) PGE2 EP1 receptor exacerbated neurotoxicity in a mouse model of cerebral ischemia and Alzheimer’s disease. Neurobiol Aging 33(9):2215–2219. doi:10.1016/j.neurobiolaging.2011.09.017

    Article  CAS  PubMed  Google Scholar 

  114. Mattammal MB, Strong R, Lakshmi VM, Chung HD, Stephenson AH (1995) Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson’s disease. J Neurochem 64(4):1645–1654

    Article  CAS  PubMed  Google Scholar 

  115. Dore-Duffy P, Ho SY, Donovan C (1991) Cerebrospinal fluid eicosanoid levels: endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system. Neurology 41(2 Pt 1):322–324

    Article  CAS  PubMed  Google Scholar 

  116. Bilak M, Wu L, Wang Q, Haughey N, Conant K, St Hillaire C, Andreasson K (2004) PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis. Ann Neurol 56(2):240–248. doi:10.1002/ana.20179

    Article  CAS  PubMed  Google Scholar 

  117. Oliveira MS, Furian AF, Royes LF, Fighera MR, Fiorenza NG, Castelli M, Machado P, Bohrer D et al (2008) Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures. Epilepsy Res 79(1):14–21. doi:10.1016/j.eplepsyres.2007.12.008

    Article  CAS  PubMed  Google Scholar 

  118. Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R (2013) Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci U S A 110(9):3591–3596. doi:10.1073/pnas.1218498110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Takemiya T, Matsumura K, Sugiura H, Maehara M, Yasuda S, Uematsu S, Akira S, Yamagata K (2010) Endothelial microsomal prostaglandin E synthase-1 exacerbates neuronal loss induced by kainate. J Neurosci Res 88(2):381–390. doi:10.1002/jnr.22195

    Article  CAS  PubMed  Google Scholar 

  120. Rojas A, Gueorguieva P, Lelutiu N, Quan Y, Shaw R, Dingledine R (2014) The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. Neurobiol Dis 70:74–89. doi:10.1016/j.nbd.2014.06.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kaiya H, Uematsu M, Ofuji M, Nishida A, Takeuchi K, Nozaki M, Idaka E (1989) Elevated plasma prostaglandin E2 levels in schizophrenia. J Neural Transm 77(1):39–46

    Article  CAS  PubMed  Google Scholar 

  122. Minghetti L, Cardone F, Greco A, Puopolo M, Levi G, Green AJ, Knight R, Pocchiari M (2002) Increased CSF levels of prostaglandin E(2) in variant Creutzfeldt-Jakob disease. Neurology 58(1):127–129

    Article  CAS  PubMed  Google Scholar 

  123. Matsuo M, Yoshida N, Zaitsu M, Ishii K, Hamasaki Y (2004) Inhibition of human glioma cell growth by a PHS-2 inhibitor, NS398, and a prostaglandin E receptor subtype EP1-selective antagonist, SC51089. J Neuro-Oncol 66(3):285–292

    Article  Google Scholar 

  124. Watanabe K (2002) Prostaglandin F synthase. Prostaglandins Other Lipid Mediat 68–69:401–407

    Article  PubMed  Google Scholar 

  125. Ito S, Sakamoto K, Mochizuki-Oda N, Ezashi T, Miwa K, Okuda-Ashitaka E, Shevchenko VI, Kiso Y et al (1994) Prostaglandin F2 alpha receptor is coupled to Gq in cDNA-transfected Chinese hamster ovary cells. Biochem Biophys Res Commun 200(2):756–762

    Article  CAS  PubMed  Google Scholar 

  126. Kitanaka J, Hasimoto H, Sugimoto Y, Negishi M, Aino H, Gotoh M, Ichikawa A, Baba A (1994) Cloning and expression of a cDNA for rat prostaglandin F2 alpha receptor. Prostaglandins 48(1):31–41

    Article  CAS  PubMed  Google Scholar 

  127. Ogawa H, Sasaki T, Kassell NF, Nakagomi T, Lehman RM, Hongo K (1987) Immunohistochemical demonstration of increase in prostaglandin F2-alpha after recirculation in global ischemic rat brains. Acta Neuropathol 75(1):62–68

    Article  CAS  PubMed  Google Scholar 

  128. Saleem S, Ahmad AS, Maruyama T, Narumiya S, Dore S (2009) PGF(2alpha) FP receptor contributes to brain damage following transient focal brain ischemia. Neurotox Res 15(1):62–70. doi:10.1007/s12640-009-9007-3

    Article  CAS  PubMed  Google Scholar 

  129. Wolfe LS, Mamer OA (1975) Measurement of prostaglandin F2alpha levels in human cerebrospinal fluid in normal and pathological conditions. Prostaglandins 9(2):183–192

    Article  CAS  PubMed  Google Scholar 

  130. Chung JI, Kim AY, Lee SH, Baik EJ (2013) Seizure susceptibility in immature brain due to lack of COX-2-induced PGF2alpha. Exp Neurol 249:95–103. doi:10.1016/j.expneurol.2013.08.014

    Article  CAS  PubMed  Google Scholar 

  131. Hara S, Miyata A, Yokoyama C, Inoue H, Brugger R, Lottspeich F, Ullrich V, Tanabe T (1994) Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells. J Biol Chem 269(31):19897–19903

    CAS  PubMed  Google Scholar 

  132. Sanchez-Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF, Martin A (2004) Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke. Stroke J Cereb Circ 35(1):163–168. doi:10.1161/01.STR.0000105391.62306.2E

    Article  CAS  Google Scholar 

  133. Gryglewski RJ (1979) Prostacyclin as a circulatory hormone. Biochem Pharmacol 28(21):3161–3166

    Article  CAS  PubMed  Google Scholar 

  134. Takechi H, Matsumura K, Watanabe Y, Kato K, Noyori R, Suzuki M, Watanabe Y (1996) A novel subtype of the prostacyclin receptor expressed in the central nervous system. J Biol Chem 271(10):5901–5906

    Article  CAS  PubMed  Google Scholar 

  135. Satoh T, Ishikawa Y, Kataoka Y, Cui Y, Yanase H, Kato K, Watanabe Y, Nakadate K et al (1999) CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain. Eur J Neurosci 11(9):3115–3124

    Article  CAS  PubMed  Google Scholar 

  136. Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Nakanishi S, Narumiya S (1991) Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature 349(6310):617–620. doi:10.1038/349617a0

    Article  CAS  PubMed  Google Scholar 

  137. Miggin SM, Kinsella BT (1998) Expression and tissue distribution of the mRNAs encoding the human thromboxane A2 receptor (TP) alpha and beta isoforms. Biochim Biophys Acta 1425(3):543–559

    Article  CAS  PubMed  Google Scholar 

  138. Gao H, Peng B, Welch WJ, Wilcox CS (1997) Central thromboxane receptors: mRNA expression and mediation of pressor responses. Am J Physiol 272(5 Pt 2):R1493–R1500

    CAS  PubMed  Google Scholar 

  139. Cazevieille C, Muller A, Meynier F, Dutrait N, Bonne C (1994) Protection by prostaglandins from glutamate toxicity in cortical neurons. Neurochem Int 24(4):395–398

    Article  CAS  PubMed  Google Scholar 

  140. Sumimoto S, Muramatsu R, Yamashita T (2014) Thromboxane A2 stimulates neurite outgrowth in cerebral cortical neurons via mitogen activated protein kinase signaling. Brain Res. doi:10.1016/j.brainres.2014.07.048

    PubMed  Google Scholar 

  141. Fagan SC, Castellani D, Gengo FM (1986) Prostanoid concentrations in human CSF following acute ischaemic brain infarction. Clin Exp Pharmacol Physiol 13(8):629–632

    Article  CAS  PubMed  Google Scholar 

  142. Steinhauer HB, Anhut H, Hertting G (1979) The synthesis of prostaglandins and thromboxane in the mouse brain in vivo. Influence of drug induced convulsions, hypoxia and the anticonvulsants trimethadione and diazepam. Naunyn Schmiedeberg’s Arch Pharmacol 310(1):53–58

    Article  CAS  Google Scholar 

  143. Hsu CY, Halushka PV, Hogan EL, Banik NL, Lee WA, Perot PL Jr (1985) Alteration of thromboxane and prostacyclin levels in experimental spinal cord injury. Neurology 35(7):1003–1009

    Article  CAS  PubMed  Google Scholar 

  144. Giulian D, Corpuz M, Richmond B, Wendt E, Hall ER (1996) Activated microglia are the principal glial source of thromboxane in the central nervous system. Neurochem Int 29(1):65–76

    Article  CAS  PubMed  Google Scholar 

  145. Iwamoto N, Kobayashi K, Kosaka K (1989) The formation of prostaglandins in the postmortem cerebral cortex of Alzheimer-type dementia patients. J Neurol 236(2):80–84

    Article  CAS  PubMed  Google Scholar 

  146. Tuppo EE, Forman LJ, Spur BW, Chan-Ting RE, Chopra A, Cavalieri TA (2001) Sign of lipid peroxidation as measured in the urine of patients with probable Alzheimer’s disease. Brain Res Bull 54(5):565–568

    Article  CAS  PubMed  Google Scholar 

  147. Yagami T, Takahara Y, Ishibashi C, Sakaguchi G, Itoh N, Ueda K, Nakazato H, Okamura N et al (2004) Amyloid beta protein impairs motor function via thromboxane A2 in the rat striatum. Neurobiol Dis 16(3):481–489. doi:10.1016/j.nbd.2004.04.013

    Article  CAS  PubMed  Google Scholar 

  148. van Kooten F, Ciabattoni G, Koudstaal PJ, Grobbee DE, Kluft C, Patrono C (1999) Increased thromboxane biosynthesis is associated with poststroke dementia. Stroke J Cereb Circ 30(8):1542–1547

    Article  Google Scholar 

  149. Urade Y, Eguchi N (2002) Lipocalin-type and hematopoietic prostaglandin D synthases as a novel example of functional convergence. Prostaglandins Other Lipid Mediat 68–69:375–382

  150. Urade Y, Kitahama K, Ohishi H, Kaneko T, Mizuno N, Hayaishi O (1993) Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Proc Natl Acad Sci U S A 90(19):9070–9074

  151. Liang X, Wu L, Hand T, Andreasson K (2005) Prostaglandin D2 mediates neuronal protection via the DP1 receptor. J Neurochem 92(3):477–486. doi:10.1111/j.1471-4159.2004.02870.x

    Article  CAS  PubMed  Google Scholar 

  152. Xu S, Venge P (2000) Lipocalins as biochemical markers of disease. Biochim Biophys Acta 1482(1–2):298–307

    Article  CAS  PubMed  Google Scholar 

  153. Mohri I, Eguchi N, Suzuki K, Urade Y, Taniike M (2003) Hematopoietic prostaglandin D synthase is expressed in microglia in the developing postnatal mouse brain. Glia 42(3):263–274. doi:10.1002/glia.10183

    Article  PubMed  Google Scholar 

  154. Hirata M, Kakizuka A, Aizawa M, Ushikubi F, Narumiya S (1994) Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene. Proc Natl Acad Sci U S A 91(23):11192–11196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Abe H, Takeshita T, Nagata K, Arita T, Endo Y, Fujita T, Takayama H, Kubo M et al (1999) Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. Gene 227(1):71–77

    Article  CAS  PubMed  Google Scholar 

  156. Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K et al (2001) Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 193(2):255–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Oida H, Hirata M, Sugimoto Y, Ushikubi F, Ohishi H, Mizuno N, Ichikawa A, Narumiya S (1997) Expression of messenger RNA for the prostaglandin D receptor in the leptomeninges of the mouse brain. FEBS Lett 417(1):53–56

    Article  CAS  PubMed  Google Scholar 

  158. Gerashchenko D, Beuckmann CT, Kanaoka Y, Eguchi N, Gordon WC, Urade Y, Bazan NG, Hayaishi O (1998) Dominant expression of rat prostanoid DP receptor mRNA in leptomeninges, inner segments of photoreceptor cells, iris epithelium, and ciliary processes. J Neurochem 71(3):937–945

    Article  CAS  PubMed  Google Scholar 

  159. Sawyer N, Cauchon E, Chateauneuf A, Cruz RP, Nicholson DW, Metters KM, O’Neill GP, Gervais FG (2002) Molecular pharmacology of the human prostaglandin D2 receptor, CRTH2. Br J Pharmacol 137(8):1163–1172. doi:10.1038/sj.bjp.0704973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Saleem S, Zhuang H, de Brum-Fernandes AJ, Maruyama T, Narumiya S, Dore S (2007) PGD(2) DP1 receptor protects brain from ischemia-reperfusion injury. Eur J Neurosci 26(1):73–78. doi:10.1111/j.1460-9568.2007.05627.x

    Article  PubMed  PubMed Central  Google Scholar 

  161. Yamashita A, Watanabe Y, Hayaishi O (1983) Autoradiographic localization of a binding protein(s) specific for prostaglandin D2 in rat brain. Proc Natl Acad Sci U S A 80(19):6114–6118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Huang ZL, Urade Y, Hayaishi O (2007) Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol 7(1):33–38. doi:10.1016/j.coph.2006.09.004

    Article  CAS  PubMed  Google Scholar 

  163. Gaudet RJ, Alam I, Levine L (1980) Accumulation of cyclooxygenase products of arachidonic acid metabolism in gerbil brain during reperfusion after bilateral common carotid artery occlusion. J Neurochem 35(3):653–658

    Article  CAS  PubMed  Google Scholar 

  164. Liu H, Li W, Rose ME, Pascoe JL, Miller TM, Ahmad M, Poloyac SM, Hickey RW et al (2013) Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites. Neurotoxicology 39:35–44. doi:10.1016/j.neuro.2013.08.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Shimizu T, Yamashita A, Hayaishi O (1982) Specific binding of prostaglandin D2 to rat brain synaptic membrane. Occurrence, properties, and distribution. J Biol Chem 257(22):13570–13575

    CAS  PubMed  Google Scholar 

  166. Wright DH, Nantel F, Metters KM, Ford-Hutchinson AW (1999) A novel biological role for prostaglandin D2 is suggested by distribution studies of the rat DP prostanoid receptor. Eur J Pharmacol 377(1):101–115

    Article  CAS  PubMed  Google Scholar 

  167. Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M (1995) Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 270(32):18910–18916

    Article  CAS  PubMed  Google Scholar 

  168. Watanabe Y, Tokumoto H, Yamashita A, Narumiya S, Mizuno N, Hayaishi O (1985) Specific bindings of prostaglandin D2, E2 and F2 alpha in postmortem human brain. Brain Res 342(1):110–116

    Article  CAS  PubMed  Google Scholar 

  169. Wu L, Wang Q, Liang X, Andreasson K (2007) Divergent effects of prostaglandin receptor signaling on neuronal survival. Neurosci Lett 421(3):253–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Koh SH, Jung B, Song CW, Kim Y, Kim YS, Kim SH (2005) 15-Deoxy-delta12,14-prostaglandin J2, a neuroprotectant or a neurotoxicant? Toxicology 216(2–3):232–243. doi:10.1016/j.tox.2005.08.015

    Article  CAS  PubMed  Google Scholar 

  171. Hata AN, Zent R, Breyer MD, Breyer RM (2003) Expression and molecular pharmacology of the mouse CRTH2 receptor. J Pharmacol Exp Ther 306(2):463–470. doi:10.1124/jpet.103.050955

    Article  CAS  PubMed  Google Scholar 

  172. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83(5):803–812

    Article  CAS  PubMed  Google Scholar 

  173. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83(5):813–819

    Article  CAS  PubMed  Google Scholar 

  174. Heneka MT, Klockgether T, Feinstein DL (2000) Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. J Neurosci Off J Soc Neurosci 20(18):6862–6867

    CAS  Google Scholar 

  175. Sundararajan S, Gamboa JL, Victor NA, Wanderi EW, Lust WD, Landreth GE (2005) Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia. Neuroscience 130(3):685–696

    Article  CAS  PubMed  Google Scholar 

  176. Inestrosa NC, Godoy JA, Quintanilla RA, Koenig CS, Bronfman M (2005) Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling. Exp Cell Res 304(1):91–104

    Article  CAS  PubMed  Google Scholar 

  177. Fitzpatrick FA, Wynalda MA (1983) Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro. J Biol Chem 258(19):11713–11718

    CAS  PubMed  Google Scholar 

  178. Rohn TT, Wong SM, Cotman CW, Cribbs DH (2001) 15-deoxy-delta12,14-prostaglandin J2, a specific ligand for peroxisome proliferator-activated receptor-gamma, induces neuronal apoptosis. Neuroreport 12(4):839–843

    Article  CAS  PubMed  Google Scholar 

  179. Shibata T, Yamada T, Kondo M, Tanahashi N, Tanaka K, Nakamura H, Masutani H, Yodoi J et al (2003) An endogenous electrophile that modulates the regulatory mechanism of protein turnover: inhibitory effects of 15-deoxy-Delta 12,14-prostaglandin J2 on proteasome. Biochemistry 42(47):13960–13968. doi:10.1021/bi035215a

    Article  CAS  PubMed  Google Scholar 

  180. Mullally JE, Moos PJ, Edes K, Fitzpatrick FA (2001) Cyclopentenone prostaglandins of the J series inhibit the ubiquitin isopeptidase activity of the proteasome pathway. J Biol Chem 276(32):30366–30373. doi:10.1074/jbc.M102198200

    Article  CAS  PubMed  Google Scholar 

  181. Ishii T, Uchida K (2004) Induction of reversible cysteine-targeted protein oxidation by an endogenous electrophile 15-deoxy-delta12,14-prostaglandin J2. Chem Res Toxicol 17(10):1313–1322. doi:10.1021/tx049860+

    Article  CAS  PubMed  Google Scholar 

  182. Uchida K, Shibata T (2008) 15-Deoxy-Delta(12,14)-prostaglandin J2: an electrophilic trigger of cellular responses. Chem Res Toxicol 21(1):138–144. doi:10.1021/tx700177j

    Article  PubMed  Google Scholar 

  183. Blanchard HC, Taha AY, Rapoport SI, Yuan ZX (2015) Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders. Prostaglandins Leukot Essent Fat Acids 96:25–30. doi:10.1016/j.plefa.2015.01.002

    Article  CAS  Google Scholar 

Download references

Conflict of Interest

The authors have declared that no competing interests exist.

Author information

Authors and Affiliations

  1. Division of Physiology, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1-7, kami-ohno, Himeji, Hyogo, 670-8524, Japan

    Tatsurou Yagami, Hiromi Koma & Yasuhiro Yamamoto

Authors
  1. Tatsurou Yagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiromi Koma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuhiro Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsurou Yagami.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yagami, T., Koma, H. & Yamamoto, Y. Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System. Mol Neurobiol 53, 4754–4771 (2016). https://doi.org/10.1007/s12035-015-9355-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9355-3

Keywords

Search

Navigation