Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition

Prosiegel, Mario; Neu, I.; Mallinger, J.; Wildfeuer, A; Mehlber, L.; Vogl, S.; Hoffmann, Georg; Ruhenstroth‐Bauer, G.

doi:10.1111/j.1600-0404.1989.tb03742.x

Cited by 26 publications

(7 citation statements)

References 4 publications

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“…But no significant difference exists in LTC4 production between MS and control peripheral blood monocytes and macrophages [118,119]. These results were also verified in the animal model of EAE [120]. Other studies, however, found normal CSF concentrations of leukotrienes [121].…”

Section: Leukotriene Receptorsmentioning

confidence: 70%

“…Another key enzyme, 5-LO, which catalyses the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid and subsequently the unstable precursor LTA4, was found to be upregulated in both MS lesions and EAE brains by microarray analysis [124]. 5-LO-specific inhibitors-treated guinea pigs showed significantly lower histological inflammation and better clinical outcome compared with controls upon EAE induction [120,125,126].…”

Section: Leukotriene Receptorsmentioning

confidence: 99%

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G protein-coupled receptors as therapeutic targets for multiple sclerosis

Xie

2012

Cell Res

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G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.

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Section: Leukotriene Receptorsmentioning

confidence: 70%

Section: Leukotriene Receptorsmentioning

confidence: 99%

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Xie

2012

Cell Res

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“…Eicosanoids include prostaglandins, leukotrienes and thromboxanes, which can act on the vasculature to cause chemoattraction of immunocompetent cells, to increase blood flow and to enhance vascular permeability [37]. Indeed, blockade of eicosanoid synthesis suppresses EAE, emphasizing their proinflammatory role in EAE [38]. In addition, annexin-1 may interfere with other, non-eicosanoid-related, proinflammatory processes.…”

Section: Discussionmentioning

confidence: 99%

Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat

Huitinga

Bauer

Strijbos

et al. 1998

Clinical and Experimental Immunology

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Annexin-1, a calcium-dependent phospholipid binding protein, has been shown to act as an endogenous central neuroprotectant, notably against cerebral ischaemic damage. In the present study we extend these findings to an animal model of multiple sclerosis, EAE, and report that endogenous annexin-1 is expressed in ED1+ macrophages and resident astrocytes localized within the lesions in the central nervous system (CNS). Intracerebroventricular (i.c.v.) administration of an NH2-terminal fragment spanning amino acids 1-188 of annexin-1 after the onset of the clinical symptoms significantly reduced both the neurological severity as well as weight loss of mild EAE. Immunoneutralization of endogenous brain annexin-1 failed to exacerbate the clinical features of EAE. Thus, although the role of endogenous annexin-1 in the pathogenesis of EAE remains to be determined, our findings suggest that annexin-1 may be of therapeutic benefit to the treatment of multiple sclerosis.

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“…The released arachidonic acids are in turn converted to prostaglandins and leukotrienes via activation of the COX and LOX pathways, respectively. These proinflammatory eicosanoids have long been suggested to contribute to the pathology of EAE (Bolton et al, 1984;Prosiegel et al, 1989;Reder et al, 1995), but the results obtained using pharmacological and genetic approaches are rather controversial. It has been shown that several COX and LOX inhibitors can reduce the severity of EAE (Marusic et al, 2008;Muthian et al, 2006;Ni et al, 2007;Ospelt et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

Vana

Ribeiro

et al. 2011

Experimental Neurology

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Inhibition of phospholipase A 2 (PLA 2 ) has recently been found to attenuate the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis (MS). However, the protective mechanisms that underlie PLA 2 inhibition are still not well understood. In this study, we found that cytosolic PLA 2 (cPLA 2 ) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA 2 is also expressed in spinal cord neurons and oligodendrocytes, there were no differences observed in these cell types between EAE and control animals. Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA 2 inhibitor, significantly reduced the clinical symptoms and inhibited the body weight loss typically found in EAE mice. AACOCF3 also attenuated the loss of mature, myelin producing, oligodendrocytes, and axonal damage in the spinal cord white matter. Nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was dramatically increased in EAE mice and attenuated by treatment with AACOCF3. These protective effects were not evident when AA861, an inhibitor of lipoxygenase, was used. In primary cultures of microglia, lipopolysaccharide (LPS) induced an upregulation of cPLA 2 , inducible nitric oxide synthase (iNOS) and components of the NADPH oxidase complex, p47phox and p67phox. AACOCF3 significantly attenuated iNOS induction, nitric oxide production and the generation of reactive oxygen species in reactive microglia. Similar to the decomposition catalyst of peroxynitrite, AACOCF3 also blocked oligodendrocyte toxicity induced by reactive microglia. These results suggest that AACOCF3 may prevent oligodendrocyte loss in EAE by attenuating peroxynitrite formation in the spinal cord white matter.Published by Elsevier Inc.

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Suppression of experimental autoimmune encephalomyelitis by dual cyclo-oxygenase and 5-lipoxygenase inhibition

Cited by 26 publications

References 4 publications

G protein-coupled receptors as therapeutic targets for multiple sclerosis

G protein-coupled receptors as therapeutic targets for multiple sclerosis

Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat

Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

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