Abstract
The aim of this study was to investigate the effects of interferon (IFN)-β1a and IFN-β1b treatment on inflammatory factors and myelin protein levels in the brain cortex of the Lewis rat experimental autoimmune encephalomyelitis (EAE), animal model of multiple sclerosis. To induce EAE, rat were immunized with inoculums containing spinal cord guinea pig homogenized in phosphate-buffered saline and emulsified in Freund’s complete adjuvant containing 110 µg of the appropriate antigen in 100 µl of an emulsion and additionally 4-mg/ml Mycobacterium tuberculosis (H37Ra). The rats were treated three times per week with subcutaneous applications of 300,000 units IFN-β1a or IFN-β1b. The treatments were started 8 days prior to immunization and continued until day 14 after immunization. The rats were killed on the 14th day of the experiment. EAE induced dramatic increase in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-concentrations and inducible nitric oxide synthase (iNOS) expression in the brain, which closely corresponded to the course of neurological symptoms and the loss of weight. Both IFN-β1b and IFN-β1a treatments inhibited the pro-inflammatory cytokines (IL-6, IL-1β, TNF-α and IFN-γ), decreased the activation of astrocytes, increased the myelin protein level in the brain cortex, and improved the neurological status of EAE rats by different mechanisms; IFN-β1a reduced iNOS expression, at least in part, by the enhancement of IL-10, while IFN-β1b diminished IL-10 concentration and did not decrease EAE-induced iNOS expression.
Highlights
Multiple sclerosis (MS) is a chronic, inflammatory neurodegenerative disease, which is characterized by demyelination and remyelination, and neuronal damage (Holz et al 2000; Stadelmann 2011; Stüve and Oksenberg 2010), with onset of disease typically occurring between the ages of 20 and 40 years (Sospedra and Martin 2005)
While the influence of IFN-β variants on the regulation of pro- and anti-inflammatory cytokines have been studied before (Graber 2007; Stępień et al 2013), this study, to the best of our knowledge, is the first to investigate the effects of these factors in the early phase of the disease
By using an inoculums-induced EAE female rat model of MS, we provide evidence that both IFN-β variants improve neurological status, reduce pro-inflammatory cytokines and astrocyte activation as well as enhance MOG and CNP-ase myelin protein levels in early stage of disease
Summary
Multiple sclerosis (MS) is a chronic, inflammatory neurodegenerative disease, which is characterized by demyelination and remyelination, and neuronal damage (Holz et al 2000; Stadelmann 2011; Stüve and Oksenberg 2010), with onset of disease typically occurring between the ages of 20 and 40 years (Sospedra and Martin 2005). After a course of the relapsing-remitting phase of the disease, most MS patients enter a phase characterized by progressive neurodegeneration associated with an irreversible variety of physical disabilities (Ireland and Monson 2011; Lucchinetti et al 2000; Trapp et al 1999). Pathological and magnetic resonance imaging studies indicate that axonal damage predominantly develops in the early stage of MS as a consequence of inflammatory process (Bendfeldt et al 2009; Comi 2000), which leads to the most numerous (~85% of cases) relapsing-remitting form of the disease (Weiner 2008).
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