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 (F(2)-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 F(2)-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 F(2)-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.