Role of blood-brain barrier in an animal model of cortical Progressive Multiple Sclerosis

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

Londres

Congreso; 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; 2016

32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis

Background: Cortical demyelinated and neurodegenerative lesions represent a hallmark of Progressive forms of Multiple Sclerosis (PFMS). Pathological studies suggested that the inflammation and neurodegeneration remained trapped into a closed blood brain barrier (BBB) in PFMS. However, several studies reported increased immune cell activation in peripheral blood of progressive MS patients. Additionally, animal studies suggested that a leaky BBB is required for the entrance of immune cells within the Central Nervous System (CNS) Objectives: To study the role of the BBB on cortical neuroinflammation and neurodegeneration after peripheral stimulation in a focal animal model of PFMS Methods: Chronic central lesions were induced in adult rats by the long term expression of interleukin 1 beta (IL-1b) in the cerebral cortex using an adenovector expressing either human IL-1b (Ad-IL1b) or betagalactosidase (Adbgal) as control. Systemic inflammation was induced by peripheral injection of either Ad-IL1b or Adbgal. We performed histological and inmmunohistochemical analysis and peripheral blood cells counting to check the systemic stimulation.Results: The long term expression of IL-1b in the cortex induces inflammation characterized by BBB breakdown, macrophages ,neutrophil and lymphocytes recruitment, demyelination, neurodegenartion, meningeal inflammation, astroglia and microglia activation peaked at 15-21 days post injection (dpi). The peripheral stimulation with Ad-IL1b at this time point, when BBB is opened, exacerbates cortical inflammation (mainly composed of neutrophils and macrophages/microglia) and neurodegeneration. At 56 dpi, the BBB is restored and the central lesion exhibited less inflammation, forming a scar composed mostly of macrophages/microglia . Interestingly, even though the BBB is restored, the peripheral stimulation induced exacerbation of the cortical neurodegenerative lesion with significant meningeal inflammation. The exacerbated cortical lesion exhibited activation of macrophages/ microglia with very few neutrophils. Conclusion: Systemic inflammation exacerbates neuroinflammation and neurodegeneration in the cortical lesion independently of BBB integrity.