Prostaglandin levels in cerebrospinal fluid from multiple sclerosis patients in remission and relapse

doi:10.1016/0165-5728(84)90002-X

Journal of Neuroimmunology

Volume 6, Issue 3, June 1984, Pages 151-159

https://doi.org/10.1016/0165-5728(84)90002-X Get rights and content

Abstract

Radioimmunoassay (RIA) techniques have been employed to determine prostaglandin (PG) levels in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients in remission and relapse and in subjects with other neurological diseases (OND). PGE and PGF₂α concentrations in spinal fluid from MS patients in relapse were significantly lower than values estimated during remission and in individuals with OND of the central nervous system (CNS). These observations are discussed in relation to the clinical state of patients with demyelinating disease together with a consideration of the concept that disordered immune mechanisms contribute a central role in the pathogenesis of MS.

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Citation Excerpt :
PGE2 then mediates its effects via activation of four EP receptors (EP1-EP4) and exerts a dual role in inflammatory processes by acting in a pro- or anti-inflammatory manner [3,4]. Previous studies revealed profound alterations in PGE2 levels and COX-2 expression in CNS-derived samples from MS patients and animals with EAE [5–8], indicating that PGE2 plays a role in the pathogenesis of MS and EAE. The role of PGE2 in the development of EAE has already been investigated using either knock-out mice or inhibitors of enzymes of the prostaglandin pathway.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory autoimmune disease model of multiple sclerosis (MS). The inflammatory process is initiated by activation and proliferation of T cells and monocytes and by their subsequent migration into the central nervous system (CNS), where they induce demyelination and neurodegeneration. Prostaglandin E2 (PGE₂) – synthesized by cyclooxygenase 2 (COX-2) – has both pro- and anti-inflammatory potential, which is translated via four different EP receptors. We hypothesized that PGE₂ synthesized in the preclinical phase by peripheral immune cells exerts pro-inflammatory properties in the EAE model. To investigate this, we used a bone marrow transplantation model, which enables PGE₂ synthesis or EP receptor expression to be blocked specifically in peripheral murine immune cells. Our results reveal that deletion of COX-2 or its EP4 receptor in bone marrow-derived cells leads to a significant delay in the onset of EAE. This effect is due to an impaired preclinical inflammatory process indicated by a reduced level of the T cell activating interleukin-6 (IL-6), reduced numbers of T cells and of the T cell secreted interleukin-17 (IL-17) in the blood of mice lacking COX-2 or EP4 in peripheral immune cells. Moreover, mice lacking COX-2 or EP4 in bone marrow-derived cells show a reduced expression of matrix metalloproteinase 9 (MMP9), which results in decreased infiltration of monocytes and T cells into the CNS. In conclusion, our data demonstrate that PGE₂ synthesized by monocytes in the early preclinical phase promotes the development of EAE in an EP4 receptor dependent manner.
Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2
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The AA cascade is stimulated during inflammatory conditions and its pathway is inhibited with NSAIDs to reduce inflammation. Activation of AA metabolism has been reported in MS [7–17]; however, due to limited and heterogeneous clinical studies, it is unclear whether AA cascade is involved in the initiation or progression of demyelination. Notably, AA is released from the cell membrane into the cytoplasm in response to proinflammatory stimuli by the activity of phospholipases A2 (PLA2) and then metabolized by cyclooxygenase (COX)-1 and -2 enzymes to bioactive pro-inflammatory prostaglandins (PGs), and by lipoxygenases (LOs) to pro-inflammatory leukotrienes (LTs) and anti-inflammatory lipoxins (LXs).
Inflammation is a physiological response to exogenous and endogenous stimuli and, together with demyelination and immune system activation, is one of the key features of multiple sclerosis (MS). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) and lipoxygenase (LO) enzymes leads to the production of proinflammatory eicosanoids, and stimulates cytokine production and activation of microglia and astrocytes, thereby contributing to MS pathology. Current therapies target the immune system but do not specifically target AA-related inflammatory pathway. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immunomodulatory therapies to treat flu-like adverse effects. Few clinical and mounting preclinical data in MS show that AA metabolism contributes to immune system activation, demyelination and motor disabilities, and administration of NSAIDs reduces these symptoms. The beneficial effect of NSAIDs seems to be a prerogative of COX-2 selective inhibitors and suggests that NSAIDs selective for COX-2 may be more effective than mixed COX-1/2 inhibitors.
Experimental autoimmune encephalomyelitis: A heterogeneous group of animal models to study human multiple sclerosis
2005, Drug Discovery Today: Disease Models
Experimental autoimmune (or allergic) encephalomyelitis (EAE), an animal model useful for the study of human multiple sclerosis, can be induced by immunization with different components of the myelin complex. In this review, the different EAE models are discussed with particular emphasis on their clinical characteristics, inflammatory mediators, as well as contributions and limitations of each variant related to the study of the progression and recuperation course phases of the disease.
Cerebrospinal fluid isoprostanes are not related to inflammatory activity in relapsing-remitting multiple sclerosis
2004, Journal of the Neurological Sciences
Oxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterised by inflammatory as well as degenerative phenomena. We previously found that cerebrospinal fluid (CSF) levels of isoprostane 8-epi-PGF_2α, a marker of free radical damage and lipid peroxidation in vivo, were elevated in MS patients. Such levels were correlated with the degree of disability and reduced in subjects under steroid therapy. Here we investigated weather the CSF isoprostane levels correlated with disease inflammatory activity. To this aim, we enrolled 41 relapsing–remitting (RR) MS patients who underwent at the same time full neurological examination, NMR-imaging brain scan and diagnostic CSF test. No evidence of correlation was found between 8-epi-PGF_2α levels and the presence of gadolinium (Gd)-enhancing NMR lesions or the time elapsed since the last relapse. We suggest that isoprostanes are not useful as surrogate inflammatory markers in MS. However, they may represent a sensitive index of degenerative phenomena, which can persist also in the absence of inflammatory activity.
Cytosolic Phospholipase A<inf>2</inf> Plays a Key Role in the Pathogenesis of Multiple Sclerosis-like Disease
2004, Neuron
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that results in motor and sensory deficits. Although MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are thought to be T cell-mediated diseases, the mechanisms underlying the lesions in the CNS are not fully understood. We propose that a strong candidate as a central mediator in evoking the complex pathological changes seen in MS and EAE is the enzyme cytosolic phospholipase A₂ (cPLA₂). One of the metabolic products of this enzyme is pro-inflammatory, while the other induces myelin breakdown, demyelination, and chemokine/cytokine expression. We provide evidence that cPLA₂ is highly expressed in EAE lesions and show that blocking this enzyme leads to a remarkable reduction in the onset and progression of EAE.
NSAID treatment suppresses VSV propagation in mouse CNS
2000, Virology
Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonic acid to prostaglandins. COX has two isoforms: COX-1, the constitutively expressed form, and COX-2, the inducible form. Prostaglandins are mediators of many critical physiological and inflammatory responses, but little is known about their roles during a viral infection in the central nervous system (CNS). We used non-selective inhibitors of COX, aspirin and indomethacin, and a selective antagonist of COX-2, celecoxib, to study the role of prostaglandins in Vesicular Stomatitis Virus (VSV) induced encephalitis. We found that the inhibition of COX antagonizes VSV propagation both in vitro and in vivo. In addition, aspirin and celecoxib both prevented the disruption of the blood brain barrier in VSV-infected mice. In vitro experiments showed that the effect of COX inhibition was at least partially mediated by increased production of Nitric Oxide (NO), a molecule known to inhibit VSV replication. When NO production was inhibited by N^ω-nitro-L-methyl-arginine-ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, the difference in viral titer between aspirin (or celecoxib)-treated and the control cells was abolished. VSV-infected mice treated with celecoxib expressed more NOS-1 and produced more NO in their CNS compared to the controls. Our data suggest that the product(s) of COX have antagonistic effect(s) on NO production in the mouse CNS.

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^☆: This study was financially supported by the Multiple Sclerosis Society of Great Britain.

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Prostaglandin levels in cerebrospinal fluid from multiple sclerosis patients in remission and relapse☆

Abstract

Prostaglandins

Biochem. Pharmacol.

Mol. Asp. Med.

J. Neuroimmunol.

Prostaglandins

Studies on the pathogenesis of multiple sclerosis — Participation of lysosomes in demyelination in the central nervous system while matter outside plaques

Europ. Neurol.

Prostaglandins in multiple sclerosis

J. Neuroimmunol.

Prostaglandin F2α levels in human cerebrospinal fluid in normal and pathological conditions

J. Neurol.

Immunosuppresive drugs in multiple sclerosis — Pro and con.

Neurology

Immunoregulatory role of prostaglandins and related lipids

Crit. Rev. Immunol.

Prostaglandin F₂α levels in human cerebrospinal fluid in normal and pathological conditions