Absence of systemic oxidative stress and increased CSF prostaglandin F_2α in progressive MS

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 F_2α [PGF_2α]) 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 PGF_2α were significantly lower in patients with progressive disease, and decreased with increasing disability score (Expanded Disability Status Scale). In contrast, CSF concentrations of PGF_2α, but not F₂-isoprostanes, were significantly higher in patients with progressive disease than OND controls (p < 0.01). The content of PGF_2α 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 PGF_2α decreased with natalizumab and methylprednisolone treatment and was unaffected by the use of nonsteroidal anti-inflammatory drug in secondary progressive MS. CSF PGF_2α 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.