Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis

Reder, Anthony T.; Thapar, Manjula; Sapugay, Anna Maria; Jensen, Mark A.

doi:10.1016/0165-5728(94)90238-0

Cited by 60 publications

(25 citation statements)

References 54 publications

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“…These results indicated that PGE 2 -EP4 signaling facilitates the EAE response, and thus, they provided genetic evidence in support of our previous data obtained with the EP4 antagonist ONO-AE3-208 in EAE (22). However, the fact that none of the other receptordeficient mouse lines showed an exaggerated EAE response did not provide a clue as to the presumed protective action of PGs in EAE suggested by previous studies with COX inhibitors (15)(16)(17)(18)(19)(20). Given that it was unclear from these experiments whether EP4 signaling functions other than during the immunization phase, we administered ONO-AE3-208 to C57BL/6 mice at a final dose of 10 mg/kg body mass per day in drinking water.…”

Section: Resultssupporting

confidence: 76%

“…Given their antiinflammatory actions, COX inhibitors have been examined for their effects on EAE in many studies. However, these drugs have been shown to exacerbate or ameliorate the disease (15)(16)(17)(18)(19)(20), leaving the role of PGs an enigma. Prophylactic use of these drugs-that is, their administration beginning the day of immunization or beforeseems to suppress EAE symptoms, whereas their therapeutic administration after or immediately before disease onset has only a mildly suppressant or an aggravating effect.…”

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confidence: 99%

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Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Esaki

Li²,

Sakata³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

106

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Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4 −/− mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2 −/− mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2 −/− mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE 2 exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.disease model | knockout mice | prostaglandin | prostaglandin receptor | multiple sclerosis M ultiple sclerosis (MS) is a chronic inflammatory disease of the CNS that primarily affects young adults (1, 2). The main pathological characteristics of MS include cell infiltration, demyelination, and axonal loss in the CNS. Although its etiology remains unclear, MS is thought to be a T cell-mediated autoimmune disease of the CNS in genetically susceptible individuals. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that can be induced in susceptible animals by immunization with myelin proteins or by injection of myelin proteinspecific CD4 + T cells (3). EAE has been studied intensively in investigations of the autoimmune response in the CNS, with recent studies having shown that T effector helper (Th) 17 or both Th17 and Th1 cells play a key role in disease pathogenesis (4-6). These Th cell subsets are also implicated in human MS (7-9).The concentrations of arachidonate metabolites such as prostaglandin (PG) E 2 and leukotriene C 4 are increased in the cerebrospinal fluid (CSF) of individuals with MS (10, 11). Arachidonic acid is liberated from phospholipids by the action of phospholipase A 2 and converted to PGs or leukotrienes by the action of cyclooxygenase (COX) and 5-lipoxygenase, respectively. Cytosolic phospholipase A 2 is a major form of phospholipase A 2 that is activated and liberates a...

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Section: Resultssupporting

confidence: 76%

mentioning

confidence: 99%

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Esaki

Li²,

Sakata³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

113

106

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“…One group of rats (Aln) was given indomethacine (water-soluble salt, from Chiesi Farmaceutici, Parma, Italy) at a dose of 1.5 mg/kg subcutaneous (s.c.) twice daily. This dose was reported not to cause malaise or weight loss in female Lewis rats [5], and was lower than the threshold dose that causes gastrointestinal lesions in rats after several days of treatment [6]. Another group of rats (Alb) was given ibuprofen (lysine salt; from Lisapharma, Erba CO, Italy) at a dose of 25 mg/kg s.c. twice daily.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Proteins of rat serum V: Adjuvant arthritis and its modulation by nonsteroidal anti-inflammatory drugs

Eberini¹,

Agnello²,

Miller³

et al. 2000

Electrophoresis

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The effect of adjuvant arthritis (AA) on the pattern of rat serum proteins includes the upregulation of haptoglobin, orosomucoid, alpha2-macroglobulin, serine protease inhibitor-3, thiostatin, alpha1-antitrypsin, C-reactive protein, and the downregulation of kallikrein-binding protein, alpha1-inhibitor III, apolipoprotein A-I, alpha2-HS-glycoprotein, albumin, apolipoprotein A-IV, transthyretin and transferrin. Minor changes (+/- 20%) are observed for Gc-globulin, ceruloplasmin, and alpha1-macroglobulin. AA thus grossly resembles the acute inflammatory response elicited by the injection of turpentine, although the changes in the levels of negative acute-phase proteins (APP) are smaller in acute inflammation. Indomethacine and ibuprofen inhibit the effects of arthritis on the synthesis of rat serum proteins in different ways: The former is, on average, three times as effective as the latter. Each drug interferes differently with different proteins. In animals without AA, both nonsteroidal anti-inflammatory drugs (NSAID) mimic the inflammatory pattern to a certain extent, with more effect on the negative than on the positive APPs. Overall, the shifts in serum protein levels parallel changes in inflammatory parameters such as joint swelling and serum interleukin-6 (IL-6) activity. Protein quantitation after two-dimensional electrophoresis (2-DE) reveals some effects of the drugs per se which escape detection by other routine tests.

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“…In particular, several studies have highlighted the role of PGE 2 and PGD 2 in the pathogenesis of EAE. For example, PGE 2 possesses vasoactive properties and has been directly and indirectly shown to modify EAE [17,51,72]. PGD 2 , the most abundant prostanoid in the CNS, has been implicated in the attenuation of inflammation and, more specifically, the regulation of microglia-astrocyte interactions and the control of demyelination, thereby providing a neuroprotective role [73][74][75].…”

Section: Discussionmentioning

confidence: 99%

“…For example, we and others have found that PGs, their precursors or compounds that alter prostanoid production had no effect or detrimental actions on the course of EAE [13,14]. In contrast, a long-acting analogue of PGE 1 and the PG synthesis inhibitor indomethacin, administered either singly or in combination, and the reversible PG inhibitor, piroxicam, reportedly suppressed EAE [15][16][17]. Furthermore, early reports indicated some neurological improvement in MS patients following long-term dietary intake of PG precursor polyunsaturated fatty acids which were also shown to be effective in models of EAE [18][19][20][21].…”

mentioning

confidence: 99%

Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE)

Ayoub

Wood²,

Hassan

et al. 2011

Inflamm. Res.

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The study examines the implications of COX isoenzyme expression over the course of CR EAE and discusses the reported relationship between PGE(2) and PGD(2) in the instigation and resolution of CNS inflammation. Consideration is also given to the treatment of CR EAE and suggests that drugs designed to limit the inflammatory effects of the PGs should be administered prior to or during the relapse phase of the disease.

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Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis

Cited by 60 publications

References 54 publications

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Proteins of rat serum V: Adjuvant arthritis and its modulation by nonsteroidal anti-inflammatory drugs

Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE)

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Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis

Cited by 60 publications

References 54 publications

Dual roles of PGE 2 -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE 2 -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Proteins of rat serum V: Adjuvant arthritis and its modulation by nonsteroidal anti-inflammatory drugs

Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE)

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Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis

Dual roles of PGE ₂ -EP4 signaling in mouse experimental autoimmune encephalomyelitis