Abstract
BackgroundFractalkine/CX3CR1 signalling has been implicated in many neurodegenerative and neurological diseases of the central nervous system (CNS). This signalling pathway plays an important role in regulating reactive oxygen species (ROS), as well as itself being altered in conditions of oxidative stress. Here, we investigated the effects of recombinant fractalkine (rCX3CL1) in models of hydrogen peroxide (H2O2)-induced demyelination and astrocyte toxicity, within organotypic cerebellar slice cultures.MethodsOrganotypic cerebellar slice cultures were generated from postnatal day 10 C57BL/6J mice to assess myelination. Immunohistochemistry was used to measure the degree of myelination. Fluorescent images were obtained using a leica SP8 confocal microscope and data analysed using ImageJ software.ResultsWe show here, for the first time, that rCX3CL1 significantly attenuated bolus H2O2-induced demyelination as measured by expression of myelin basic protein (MBP) and attenuated reduced vimentin expression. Using the GOX-CAT system to continuously generate low levels of H2O2 and induce demyelination, we observed similar protective effects of rCX3CL1 on MBP and MOG fluorescence, although in this model, the decrease in vimentin expression was not altered.ConclusionsThis data indicates possible protective effects of fractalkine signalling in oxidative stress-induced demyelination in the central nervous system. This opens up the possibility of fractalkine receptor (CX3CR1) modulation as a potential new target for protecting against oxidative stress-induced demyelination in both inflammatory and non-inflammatory nervous system disorders.
Highlights
Fractalkine/Fractalkine receptor (CX3CR1) signalling has been implicated in many neurodegenerative and neurological diseases of the central nervous system (CNS)
We have shown that glucose oxidase-catalase (GOX-catalase solution (CAT)) and bolus Hydrogen peroxide (H2O2) can cause demyelination, which is attenuated by the multiple sclerosis (MS) drug, FTY720/Gilenya [23]
After 18 h of bolus H2O2 treatment, there is a significant decrease in myelin basic protein (MBP) fluorescence (59.6 ± 2.5%), which was significantly attenuated in groups pre-treated with Recombinant fractalkine (rCX3CL1) (94.5 ± 10.3%) (Student’s t test, ###p < 0.001, and oneway analysis of variance (ANOVA) and Tukey’s post hoc test, *p < 0.05) (Fig. 1B(i))
Summary
Fractalkine/CX3CR1 signalling has been implicated in many neurodegenerative and neurological diseases of the central nervous system (CNS). Fractalkine (CX3CL1) and its receptor, fractalkine receptor (CX3CR1), are constitutively expressed in the central nervous system. This is in contrast to most other chemokines, whose expression in the brain is only detected during inflammation [1,2,3]. CX3CR1 has been localised to microglia [1, 5] and shown to be expressed intracellularly by neurons [5]. In the rodent experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis (MS), an increase in astrocytic levels of fractalkine was observed at sites of inflammation, while neuronal fractalkine remained unchanged.
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