Eicosenoids Modify Experimental Allergic Encephalomyelitis

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

doi:10.1097/00045391-199509000-00020

Cited by 10 publications

(9 citation statements)

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“…While AA metabolism has been shown to be altered in the EAE model of demyelination, which is dependent on the activation of the immune system [10, 11, 22–25], this is the first demonstration that the AA cascade is altered in a model for primary demyelination, in a time- and cell type-dependent fashion.…”

Section: Discussionmentioning

confidence: 96%

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

Palumbo¹,

Toscano²,

Parente³

et al. 2011

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Phospholipases A2 (PLA2) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of proinflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA2 enzymes and the terminal prostaglandin levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for six weeks to allow spontaneous remyelination. We found that after 4–6 weeks of cuprizone, sPLA2(V) and cPLA2, but not iPLA2(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA2(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE2, PGD2, PGI2 and TXB2 were also increased during demyelination. During remyelination, none of the PLA2 isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE2, PGI2, and PGD2 levels returned to normal, whereas TXB2 was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time-dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and suggests that sPLA2(V) is the major isoform contributing to AA release.

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Section: Discussionmentioning

confidence: 96%

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

Palumbo¹,

Toscano²,

Parente³

et al. 2011

Prostaglandins, Leukotrienes and Essential Fatty Acids

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“…However, their results with nimesulid stand in contrast to investigations by Muthian et al, which demonstrated therapeutic effects with 4 different COX-2 inhibitors [36]. Other non-specific COX-2 inhibitors (indomethacin) have also been shown to have therapeutic effects in EAE [38,39]. Other enzymes involved in the generation of prostanoids have been implicated in the pathology of EAE.…”

Section: Discussionmentioning

confidence: 97%

Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

Carlson

Rojas

Redd

et al. 2010

J Neuroinflammation

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BackgroundWe previously found that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of multiple sclerosis (MS) (Carlson et al. J.Neuroimmunology 2006, 149:40). This suggests that COX-2 may contribute to death of oligodendrocytes.ObjectiveThe goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.MethodsThe potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes in vitro. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death.ResultsCOX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death in vitro. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA). Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a significant decrease in sensitivity to KA induced death.ConclusionsCOX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.

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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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Eicosenoids Modify Experimental Allergic Encephalomyelitis

Cited by 10 publications

References 0 publications

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

Cyclooxygenase-2 expression in oligodendrocytes increases sensitivity to excitotoxic death

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

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