Journal of Clinical & Experimental Pharmacology

Using a new vinyl sulfone as a promising therapeutic strategy to prevent microglia-mediated inflammation in Alzheimer's disease

World Congress on Pharmacology

July 20-22, 2015 Brisbane, Australia

Dora Brites, Falcao A S, Lidonio G, Vaz A R, Santos M and Moreira R

Posters-Accepted Abstracts: Clin Exp Pharmacol

Abstract:

Alzheimer�??s disease (AD) is the most common neurodegenerative disorder in the elderly, characterized by amyloid-beta (Abeta) peptide deposits and chronic inflammation. Microglia was shown to be activated in the early stage of AD and the alarming High-Mobility Group Box 1 (HMGB1) to mediate neuroinflammation. We aimed to investigate whether vinyl sulfone (VS) with anti-cathepsin S, B and L activity was able to inhibit the expression of HMGB1 and if so, to modulate microgliarelated inflammatory signaling pathways. The microglia cell line N9 was incubated with 1 μM Abeta alone or in the presence of 20 μM VS, for 24 h. Cell viability was assessed by propidium iodide staining and neuroinflammation by determining the activity of matrix metalloproteinases (MMPs)-9 and MMP-2, the expression of HMGB1, as well as its toll-like receptor-4 (TLR-4). We additionally evaluated the microRNA (miR)-155 (up-regulated by HMGB1) and miR-146a (up-regulated by IL- 1β), which are associated with inflammation. Data showed that Abeta increased microglial necrotic death (1.9-fold, p<0.01), MMP-2 and MMP-9 activation (~1.6-fold, p<0.01), as well as HMGB1 expression (>2.5-fold, p<0.01, protein/mRNA), without causing alteration on the TLR4 protein expression. Abeta induced the expression of miR-155 (1.8-fold, p<0.05) and marginally of miR-146 (1.3-fold). Interestingly, VS was able to prevent Abeta-related loss of microglia viability (p<0.01) and its immunostimulation, sustaining the values of MMP-2, MMP-9, HMGB1 and miR-155 (all p<0.05), including miR-146, at control levels (without Abeta). Our study reveals that VS prevents Abeta-induced microglia dysfunction and inflammation and suggests its therapeutic potential in neuroinflammatory diseases.