Absence of systemic oxidative stress and increased CSF prostaglandin F _2α in progressive MS

Abstract

Objective:We aimed to investigate the role of oxidative stress in the progression of multiple sclerosis (MS).Methods: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 biomarkers of inflammation (chemokine ligand 13; matrix metalloproteinase-9; osteopontin) and axonal damage (neurofilament light protein).Results:Compared with OND controls, plasma concentrations of F2-isoprostanes and PGF2α were significantly lower in patients with progressive disease, and decreased with increasing disability score (Expanded Disability Status Scale). In contrast, CSF concentrations of PGF2α, but not F2-isoprostanes, were significantly higher in patients with progressive disease than OND controls (p < 0.01). The content of PGF2α 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 PGF2α decreased with natalizumab and methylprednisolone treatment and was unaffected by the use of nonsteroidal anti-inflammatory drug in secondary progressive MS. CSF PGF2α did not associate with validated CSF markers of inflammation and axonal damage that themselves did not associate with the Expanded Disability Status Scale.Conclusions: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.

Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis

“…The most discriminant metabolites found herein represent novel findings in MS to a large extent; 5,6-DH-PGF 1 is a prostaglandin. Prostaglandin F 2α has previously been shown to decrease in plasma and increase in CSF of progressive MS patients compared to other neurological diseases 42 , 43 , suggesting that prostaglandins may be involved in the pathology of MS. Furthermore, indolepyruvate is involved in tryptophan metabolism, where it catalyzes the nonoxidative decarboxylation of 3-indolepyruvate to 3-indoleacetaldehyde.…”

Suppressed oligodendrocyte steroidogenesis in multiple sclerosis: Implications for regulation of neuroinflammation

“…Both innate and adaptive immunity participate in the pathogenesis of MS and its established model, experimental autoimmune encephalomyelitis (EAE), as indicated by the presence of activated lymphocytes and increased cytokine and chemokine production by macrophages, microglia and astrocytes (Gomez Perdiguero, Schulz, & Geissmann, ; Grebing et al, ; Hendriks, Teunissen, de Vries, & Dijkstra, ; Mayo, Quintana, & Weiner, ). Mechanisms of demyelination and ensuing neurodegeneration (axonal and neuronal damage) remain uncertain although inflammatory molecules including cytokines, chemokines, prostaglandins, reactive oxygen species (Caruso et al, ; Lassmann, ) and proteases have been implicated in demyelination and axonal/neuronal injury (Huber & Irani, ; Lam et al, ; Radbruch et al, ; Takahashi, Giuliani, Power, Imai, & Yong, ). Several mechanisms by which inflammatory mediators contribute to cytotoxicity have been identified, including exacerbation of glutamate excitotoxicity by proinflammatory cytokines, damage to DNA, lipids, and proteins by ROS, and induction of apoptosis by death‐receptors ligands (Kharel, McDonough, & Basu, ; Ohl, Tenbrock, & Kipp, ; Sulkowski, Dabrowska‐Bouta, Kwiatkowska‐Patzer, & Struzynska, ).…”

The Evaluation of Oxidative Stress Parameters in Serum Patients with Relapsing‐Remitting Multiple Sclerosis Treated with II‐Line Immunomodulatory Therapy

“…It seems that RRMS, secondary progressive MS, and primary progressive MS patients and the control group should be compared in order to better assess the severity of the disease and OS. For example, Lam et al observed that plasma concentrations of F2-isoprostanes and prostaglandin F2alpha (PGF2 α ) decreased and were related to the increased EDSS in patients with the progressive disease [ 72 ]. That study involved patients with the progressive disease where the processes of neurodegeneration predominated over inflammatory processes.…”