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The objective of this study was to evaluate the association between glutamate (Glu) levels in cerebrospinal fluid (CSF) at disease onset and disease progression during follow up in a cohort of multiple sclerosis (MS) patients. Glu level was measured at disease onset (first relapse). MRI was obtained at baseline and follow-up (every 12 months) to determine the percent of brain volume change (PBVC), cortical thickness (CT), and T2 lesion volume (T2LV). The primary predictors of interest were baseline CSF Glu levels, PBVC and CT, as well as clinical disease progression [measured by Expanded Disability Status Scale (EDSS) and annualized relapse rate] during follow-up. A total of 26 MS patients were included. Mean concentration of Glu in CSF at diagnosis was 5.3 ± 0.4 uM/l. A significant association was observed between higher baseline levels of Glu and an increase in EDSS during follow up (b = 1.06, 95%CI 0.47-1.66, p = 0.003) as well as PBVC (b = -0.71 95%CI -0.56-1.38, p = 0.002) and CT (b = -0.15, 95%CI -0.06-0.33, p = 0.01). We did not observe an association between baseline Glu levels and relapse rate or T2LV during follow-up (b = 0.08, 95%CI -0.11-0.43, p = 0.11 and b = 195, 95%CI -39-330, p = 0.22, respectively). Higher Glu concentrations at disease onset were associated with an increase in PBVC and EDSS progression during follow-up in MS patients.El objetivo del trabajo fue evaluar la asociación entre el nivel de glutamato en el líquido cefalorraquídeo (LCR) al inicio de la enfermedad y la progresión de la enfermedad durante el seguimiento en una cohorte de pacientes con esclerosis múltiple (EM). Se determinaron niveles de glutamato (Glu) en LCR al inicio de la enfermedad. Se realizó una resonancia basal y durante el seguimiento cada 12 meses con el objeto de determinar el porcentaje de cambio de volumen cerebral (PCVC), grosor cortical (GC) y volumen lesional cerebral en secuencia T2 (VLT2). Los predictores primarios de interés fueron los niveles basales de Glu en LCR, PCVC Y GC, así como la progresión clínica de la enfermedad [medida por Expanded Disability Status Scale (EDSS) y tasa anual de recaídas]. Un total de 26 pacientes fueron incluidos. La concentración media de Glu fue de 5.3 ± 0.4 uM/l. Se encontró una asociación significativa entre concentraciones basales elevadas de Glu y la progresión del EDSS (b = 1.06, IC 95% 0.47-1.66, p = 0.003), así como también el PCVC (b = -0.71, IC 95% -0.56-1.38, p = 0.002) y CG (b = -0.15, IC 95% -0.06-0.33, p = 0.01). No se encontró asociación entre los niveles de Glu y la tasa anual de recaídas como tampoco el VLT2 (b = 0.08, IC 95% -0.11-0.43, p = 0.11 y b = 195, IC -39-330, p = 0.22, respectivamente). Los niveles aumentados de Glu se asociaron con un mayor cambio en el PCVC y progresión del EDSS durante el seguimiento.

Myelin-associated glycoprotein (MAG) is a key molecule involved in the nurturing effect of myelin on ensheathed axons. MAG also inhibits axon outgrowth after injury. In preclinical stroke models, administration of a function-blocking anti-MAG monoclonal antibody (mAb) aimed to improve axon regeneration demonstrated reduced lesion volumes and a rapid clinical improvement, suggesting a mechanism of immediate neuroprotection rather than enhanced axon regeneration. In addition, it has been reported that antibody-mediated crosslinking of MAG can protect oligodendrocytes (OLs) against glutamate (Glu) overload by unknown mechanisms.To unravel the molecular mechanisms underlying the protective effect of anti-MAG therapy with a focus on neuroprotection against Glu toxicity.MAG activation (via antibody crosslinking) triggered the clearance of extracellular Glu by its uptake into OLs via high affinity excitatory amino acid transporters. This resulted not only in protection of OLs but also nearby neurons. MAG activation led to a PKC-dependent activation of factor Nrf2 (nuclear-erythroid related factor-2) leading to antioxidant responses including increased mRNA expression of metabolic enzymes from the glutathione biosynthetic pathway and the regulatory chain of cystine/Glu antiporter system xcMAG activation triggers Glu uptake into OLs under conditions of Glu overload and induces a robust protective antioxidant response.