The antibacterial drug Rifampicin prevents a-Synuclein-mediated microglial cell activation

RITA RAISMAN; ACUÑA, L; SABAH HAMADAT; CORBALÁN NATALIA S.; FLORENCIA GONZÁLEZ; JEREMY ROCCA; ROSANA CHEHÍN; DULCE PAPY; SEPÚLVEDA DIAZ; PATRICK MICHEL

Edinburgh

Congreso; XIII European Metting on Glial Cells in Health and Diseases; 2017

GLIA

Microglial cells are resident macrophages of the brain. In chronic neurodegenerative conditions, such as Parkinson´s diseases (PD), microglial cells undergo long-lasting activation and as a result participate activelyin neurodegeneration. Rifampicin, an antibacterial drug, used for the treatment of tuberculosis,meningococcal meningitis and leprosy was reported previously to have anti-inflammatory effects. Thus, wehypothesized that Rifampicin, could exert similar effects in a situation where the activation of microglial cellsis induced by 􀄮-Synuclein aggregates (ASa), a pro-inflammatory trigger in PD. To test this possibility, weestablished a culture model of primary microglial cells purified from post-natal C57BL/6J mouse pup brainsand tested the impact of Rifampicin in cultures that were challenged with ASa for a period of 24 h. Conditionedmedia were then collected to perform ELISA assays and measure levels of pro-inflammatory cytokines (TNF-􀄮, IL-1􀈕, IL-6). Adherent cells were either fixed for immunostaining procedures or lysed for western blotimmunoassays. The effects of test treatments on microglial cell proliferation were monitored through theincorporation of [3H]-thymidine. Cortical neurons purified from C57BL/6J mouse brain embryos were alsochallenged with a medium conditioned by microglial cell cultures treated or not with ASa. Neuronal viabilitywas measured using the cell counting kit-8 (CCK-8) and LDH release.Our data show that Rifampicin strongly reduced the inflammatory response of microglial cells exposed toASa. In particular, Rifampicin caused a strong decrease (i) in the expression of the calcium-binding proteinIba-1, (ii) in the production and release of TNF-􀄮 and IL-6, and (iii) in cell proliferation. The effects ofRifampicin were reproduced by inhibition of PI3K/pAKT-dependent signaling. Importantly, Rifampicin also