A new animal model of cortical neuroinflammation induces neurodegeneration and cognitive impairment as an approach to the progressive forms of multiple sclerosis

BERENICE ANABEL SILVA; MARIA CELESTE LEAL; MARIA ISABEL FARIAS; FERNANDO J PITOSSI; CARINA C FERRARI

Barcelona

Congreso; 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 2015

ECTRIMS

Background: Progressive forms of Multiple Sclerosis (PFMS) are unresponsive to conventional immunomodulatory treatments. Additionally, the pathology of the PFMS is still unknown. Neuroinflammation and cortical lesions, key features of these forms, could contribute to physical disabilities and cognitive impairment (CI). Therefore, the cortical microenvironment, influence the degree of inflammation, tissue damage , the repair of the lesions and the clinical outcome. We developed a model of chronic and focal inflammatory demyelination/remyelination triggered by the long term expression of the pro-inflammatory cytokine, interleukin-1beta (IL-1b), which exhibited regional differences to IL-1b response, in particular between striatum and Substantia Nigra.Objectives: To study the effect of the chronic expression of IL-1 in the cortex of adult rats and the influence of peripheral pro-inflammatory stimulus on these lesions. Methods: The chronic expression of IL-1 is achieved by an adenovector expressing human IL-1b (AdIL-1b) or betagalactosidase (Adbgal) as a control. We performed behavioral, histological, immunohistochemical and molecular analysis. Results: The long term expression of IL-1 in the cortex induces inflammation characterized by neutrophil and macrophages recruitment, edema, demyelination, astro and microglia activation. The inflammation peaked at 15-21 days post injection (dpi) and the lesion is restored by 30dpi. These results are correlated with a worse performance in the behavioral and anxiety test at 15-21dpi and are improved as far as the lesion is recovered (30 days). The peripheral stimulation exacerbates the cortical damage, with an increased glial and inflammatory response, CI and neurodegeneration.Conclusions: Considering that no effective treatment is available for PFMS, the pathophysiology of the PFMS and its relationship with clinical features need to be better understood. We developed a new experimental model of cortical inflammation and neurodegeneration associated with CI and anxiety-like behavior. This simple model could allow the identification of pathological mechanisms of the PFMS, which could be use as targets for designing specific PFMS treatments.