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Absence of systemic oxidative stress and increased CSF prostaglandin F2? in progressive MS.

ABSTRACT: We aimed to investigate the role of oxidative stress in the progression of multiple sclerosis (MS).We determined by liquid chromatography-tandem mass spectrometry nonenzymatic (F2-isoprostanes) and enzymatic oxidation products of arachidonic acid (prostaglandin F2? [PGF2?]) in plasma and CSF of 45 controls (other neurologic disease [OND] with no signs of inflammation) and 62 patients with MS. Oxidation products were correlated with disease severity and validated biomarkers of inflammation (chemokine ligand 13; matrix metalloproteinase-9; osteopontin) and axonal damage (neurofilament light protein).Compared with OND controls, plasma concentrations of F2-isoprostanes and PGF2? were significantly lower in patients with progressive disease, and decreased with increasing disability score (Expanded Disability Status Scale). In contrast, CSF concentrations of PGF2?, but not F2-isoprostanes, were significantly higher in patients with progressive disease than OND controls (p < 0.01). The content of PGF2? in CSF increased with disease severity (p = 0.044) and patient age (p = 0.022), although this increase could not be explained by age. CSF PGF2? decreased with natalizumab and methylprednisolone treatment and was unaffected by the use of nonsteroidal anti-inflammatory drug in secondary progressive MS. CSF PGF2? did not associate with validated CSF markers of inflammation and axonal damage that themselves did not associate with the Expanded Disability Status Scale.Our data suggest that MS progression is associated with low systemic oxidative activity. This may contribute to immune dysregulation with CNS inflammation accompanied by increased local cyclooxygenase-dependent lipid oxidation.

SUBMITTER: Lam MA

PROVIDER: S-EPMC4929888 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Absence of systemic oxidative stress and increased CSF prostaglandin F2α in progressive MS.

Lam Magda A MA Maghzal Ghassan J GJ Khademi Mohsen M Piehl Fredik F Ratzer Rikke R Romme Christensen Jeppe J Sellebjerg Finn Thorup FT Olsson Tomas T Stocker Roland R

Neurology(R) neuroimmunology & neuroinflammation 20160630 4

<h4>Objective</h4>We aimed to investigate the role of oxidative stress in the progression of multiple sclerosis (MS).<h4>Methods</h4>We determined by liquid chromatography-tandem mass spectrometry nonenzymatic (F2-isoprostanes) and enzymatic oxidation products of arachidonic acid (prostaglandin F2α [PGF2α]) in plasma and CSF of 45 controls (other neurologic disease [OND] with no signs of inflammation) and 62 patients with MS. Oxidation products were correlated with disease severity and validated ...[more]

PMID: 27386506

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Project description:Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient in DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both group of aged mice, scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging.

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Dataset Information

Absence of systemic oxidative stress and increased CSF prostaglandin F2? in progressive MS.

Publications

Absence of systemic oxidative stress and increased CSF prostaglandin F2α in progressive MS.

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