Rifampicin suppresses alpha-synuclein induced microglial activation and improve neuron survival against inflammation

NATALIA SOLEDAD CORBALAN; ROSANA CHEHIN; RITA RAISMAN-VOZARI; SABAH HAMADAT; JEREMY ROCCA; DULCE PAPY- GARCIA; LEONARDO ACUÑA; FLORENCIA GONZALEZ; PATRICK P. MICHEL

Florianopolis

Congreso; Joint Meeting Neurotoxicity Society and International Neurotoxicology Association; 2017

Neurotoxicity Society and International Neurotoxicology Association

Microglial cells are the resident immune cells of the brain parenchyma. Sustained activation of microglia isknown to play a role in the progression of neurodegenerative diseases such as Parkinson?s disease (PD). Ithas been suggested that the modulation of microglial activation could prevent neuronal demise and thus theprogression of neurodegeneration. Based on clinical studies in the context of infectious diseases whereRifampicin seems to protect patients from neurodegeneration, we hypothesize that Rifampicin, could exert aneuroprotective effect by suppressing microglial activation induced by endogenous pro-inflammatorymediators, such as alpha-synuclein aggregates (ASa). Primary microglial cells purified from post-natal day 1C57BL/6J mouse pup brains were pre-treated or not with Rifampicin, then challenged with ASa and incubatedfor 24 h. Conditioned media were collected to perform ELISA assays to measure cytokine levels (TNF-α, IL-1b,IL-6). Adherent cells were either fixed for immunostaining procedures or lysed for western blot assays. Themodulatory effect of drugs on cell proliferation was also followed by thymidine incorporation. Cortical neuronspurified from C57BL/6J mouse embryos were challenged to microglial induced conditioned media. The viabilitywas measured using CCK-8 and LDH release. Rifampicin readily reduced prototypical markers of inflammationinduced by ASa such as (i) Iba-1 expression, (ii) TNF-α and IL-6 production and release, (iii) morphologicalchanges, and (iv) cell proliferation, by blocking PI3K/pAKT signaling pathway, (v) neuron survival. Globally, ourresults suggest that Rifampicin inhibits microglial activation induced by ASa. We thus propose that Rifampicincould be used as a novel treatment for neurodegenerative diseases such as PD