Rifampicin protects PC12 cells against MPP+-induced apoptosis and inhibits the expression of an α-Synuclein multimer

The potential cytoprotective effects of the anti-leprosy antibiotic rifampicin were investigated in rat pheochromocytoma (PC12) cells prior to intoxication with 1-Methyl-4-phenyl pyridinium (MPP+). MPP+ induced both apoptotic and necrotic cell death, and increased the expression of a 57 kDa species of α-Synuclein. This species of α-Synuclein is larger than the monomer, and is therefore an oligomer or an aggregated form of the protein. Rifampicin significantly increased survival of these catecholaminergic cells in a concentration-dependent manner. The expression of the higher molecular mass α-Synuclein was increased by MPP+ exposure, and its expression was inversely related to cell survival in the rifampicin-treated cells. Importantly, rifampicin suppressed apoptosis almost completely, without shifting the death cascade to necrosis, which is a problem that has been reported with caspase inhibitors of apoptosis (Hartmann, A., Troadec, J.D., Hunot, S., Kikly, K., Faucheux, B.A., Mouatt-Prigent, A., Ruberg, M. Agid, Y., Hirsch, E.C., 2001. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J. Neurosci. 21, 2247–2255). These results suggest that rifampicin improves survival of catecholamine- and α-Synuclein-containing cells, which degenerate in Parkinson's disease (PD), and thus may be therapeutic in this disease.