CONICET | Buscador de Institutos y Recursos Humanos

Microglial cells are the resident immune cells of the brain parenchyma. Sustained activation of microglia is known to play a role in the progression of neurodegenerative diseases such as Parkinson?s disease (PD). It has been suggested that the modulation of microglial activation could prevent neuronal demise, and thus the progression of neurodegeneration. Based on clinical studies in the context of infectious diseases where Rifampicin seems to protect patients from neurodegeneration, we hypothesize that rifampicin quinone (RifQ), an autoxidation product of Rifampicin, is responsible for a neuroprotective effect by suppressing microglial activation induced by endogenous pro-inflammatory mediators, such as α-synuclein fibrils (αSf). Primary microglial cells purified from post-natal day 1 C57BL/6J mouse pup brains were pre-treated or not with RifQ, then challenged with αSf and incubated for 24 h. Conditioned media were collected to measure cytokine levels (TNF-α, IL-1b, IL-6) by ELISA assays. Adherent cells were either fixed for immunostaining procedures or lysed for western blot assays. The modulatory effect of drugs on cell proliferation was also followed by thymidine incorporation. Cortical neurons purified from C57BL/6J mouse embryos were challenged to microglial induced conditioned media. The viability was measured using CCK-8 and LDH release. RifQ readily reduced prototypical markers of inflammation induced by αSf such as (i) Iba-1 expression, (ii) TNF-α and IL-6 release, (iii) morphological changes, and (iv) cell proliferation, by blocking PI3K/pAKT signaling pathway, leading to neuron survival. Globally, our results suggest that RifQ inhibits microglial activation induced by αSf. We thus suggest that RifQ should be studied in depth to propose it as a novel treatment for neurodegenerative diseases such as PD.