Rifampicin protects PC12 cells against MPP+-induced apoptosis and inhibits the expression of an alpha-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 alpha-Synuclein. This species of alpha-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 alpha-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 alpha-Synuclein-containing cells, which degenerate in Parkinson's disease (PD), and thus may be therapeutic in this disease.
Xu
Jie
J
Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Wei
Chuangzhen
C
Xu
Changqing
C
Bennett
M Catherine
MC
Zhang
Guohua
G
Li
Fangcheng
F
Tao
Enxiang
E
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000633:toxicity; D007917:Leprostatic Agents / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D011487:Protein Conformation / Q000187:drug effects; D051381:Rats; D012293:Rifampin / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D007917:Leprostatic Agents; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D015655:1-Methyl-4-phenylpyridinium; D012293:Rifampin