A NOVEL MODEL OF CORTICAL INFLAMMATION: AN APPROACH FOR ADDRESSING MULTIPLE SCLEROSIS PATHOLOGY

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

Rio de Janeiro

Congreso; IBRO 9Th; 2015

International Brain Research Organiztion (IBRO)

Key aspects of Multiple Sclerosis (MS) pathophysiology remain obscure, which prevents the development of more efficient treatments. MS exhibits different forms: relapsing remitting (RRMS), primary and secondary progressive (PPMS, SPMS). Even though neuroinflammation is hallmark in every form of the disease, immunomoduladory treatments are beneficial in the early stages of MS, but ineffective in PPMS and SPMS. Interestingly, cortical lesions were described mostly in PPMS and SPMS patients, which contribute to physical disability and cognitive impairment that characterize the progressive forms. On the other hand, it was demonstrated that a peripheral proinflammatory stimulus can exacerbate the damage produced by central inflammatory lesions (Ferrari et al., 2006, Murta el al., 2014) ). In addition, we developed a model of chronic and focal inflammatory triggered by the long term expression of one inflammatory cytokine, interleukin-1beta (IL-1b), which present regional differences (Ferrari et al., 2006, Murta et al., 2012).The aim of this project is to study the effect of systemic inflammation on an ongoing pro-inflammatory cortical lesion, analyzing its effects on histological characteristics and cognitive behaviour. We hypothesize that peripheral stimulation exacerbates the cortical microenvironment, and influence the degree of inflammation, tissue damage and, as a consequence, cognitive deterioration.We used an adenovector expressing human IL-1b (AdIL-1b) or betagalactosidase (Adbgal) to induce chronic IL-1b expression in the cortex and the same AdIL-1b to induce systemic inflammation. We performed behavioral, histological, immunohistochemical and molecular analysis to peripherally stimulated animals and compare them with non stimulated ones. The peripheral inflammation exacerbated the cortical lesion, demonstrated by an increased inflammatory response, characterized by an increment in neutrophils and macrophages compared to control animals. The micro and astroglia response is also exacerbated compared to non-peripherally stimulated animals. Finally, cognitive impairment was also increased in the animals receiving pro-inflammatory stimuli.In summary, pro-inflammatory stimuli exacerbate both the inflammatory response and concomitantly the performance in the cognitive behavioural tests. This new model allows to study the influence of systemic stimulation on the Progressive Multiple Sclerosis cortical lesions and could help to develop more specific therapeutic approaches by revealing crucial aspects of MS pathophysiology