The first author (RB) received special training in neuroimmune diseases in his Hospital. The first author treated the patients and collected the clinical information and writes the manuscript. GT, UT, CN, y MT provided guidance for the diagnosis and treated the patient as part of the medical team. PP performed the neurophysiological study. SC contributed to ending of the manuscript and approved the final version.

Background: Major role of oxidative stress in the pathogenesis of neurodegenerative diseases have been suggested, being mitochondria one of the main sources of ROS. Aim: In the present work, we have studied the antioxidant effect of fingolimod phosphate (FP) on neuronal mitochondrial function and morphology using a model of mitochondrial oxidative damage induced by menadione (Vitk3). Methods: SN4741 neuronal cells were grown (70-80% confluence) and used as control (nontreated cells) or treated cells with Vitk3 15 µM alone or in presence of FP 50 nM during 4 hours. Mitochondrial membrane potential (MMP), cytochrome c oxidase (COX) activity, mitochondrial oxygen consumption rate (OCR), mitochondrial distribution (MTG) and morphology (EM) were analysed. Statistical differences were determined using one-way ANOVA. Results: Vitk3 incubation produces a dramatical decrease in MMP compared to control (43.7 %); this can be almost totally reverted by the co-incubation of Vitk3 in presence of FP (p<0.05). A 20.7 % decrease in COX activity has been found after Vitk3 incubation, again this effect was counteracted when Vitk3 and FP are combined, restoring COX activity to control levels (p<0.05). Vitk3 incubation triggers initially an increase in OCR, decreasing dramatically (61%) after 4 hours. In experiments co-incubating Vitk3 in presence of FP, the OCR decrease found was reduced to only 17% (p<0.05). In experiments with MitoTracker™ Green, we found a change in the network pattern distribution after Vitk3 administration that partially disappears when co-incubated in presence of FP. Almost all the mitochondria treated with Vitk3 show ultrastructural alterations at the electron microscopy level while normal mitochondria can be found when Vitk3 and FP are combined. Conclusion: FP protects against the mitochondrial damage induced by Vitk3, as seen by the results obtained in mitochondrial functional markers, distribution and morphology.

The lysophosphatidic acid LPA₁ receptor has recently been involved in the adaptation of the hippocampus to chronic stress. The absence of LPA₁ receptor aggravates the chronic stress-induced impairment of both hippocampal neurogenesis and apoptosis that were accompanied with hippocampus-dependent memory deficits. Apoptotic death and neurogenesis in the hippocampus are regulated by oxidative stress. In the present work, we studied the involvement of LPA₁ receptor signaling pathway in the regulation of the hippocampal redox after chronic stress. To this end, we used malpar1 knockout (KO) and wild-type mice assigned to either chronic stress (21 days of restraint, 3 h/day) or control conditions. Lipid peroxidation, the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX), as well as mitochondrial function stimulation, monitored through the activity of cytochrome c oxidase (COX), were studied in the hippocampus. Our results showed that chronic immobilization stress enhanced lipid peroxidation as well as the activity of the antioxidant enzymes studied (CAT, SOD, and GPX). This effect was only observed in absence of LPA₁ receptor. Furthermore, only malpar1 KO mice submitted to chronic stress exhibited a severe downregulation of the COX activity, suggesting the presence of mitochondrial damage. Altogether, these results suggest that malpar1 KO mice display enhanced oxidative stress in the hippocampus after chronic stress. This may be involved in the hippocampal abnormalities observed in this genotype after chronic immobilization, including memory, neurogenesis, and apoptosis.

The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.