title: Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells.
abstract: In this study, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in PC12 cells. Coincubation of PC12 cells with indomethacin, ibuprofen, ketoprofen, or diclofenac, but not aspirin or N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide (NS-398), significantly potentiated the MPP(+)-induced cell death. In contrast, these NSAIDs had no effect on rotenone-induced cell death. The potentiating actions of these NSAIDs were not suppressed by treatment with phenyl-N-butyl-nitrone, a radical scavenger; N-acetyl-l-cysteine, an antioxidant; Ac-DEVD-CHO, a selective caspase-3 inhibitor; or 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective antagonist of peroxisome proliferator-activated receptor gamma. Furthermore, we observed that DNA fragmentation, which is one of the hallmarks of apoptosis, was not induced by coincubation with MPP(+) and NSAIDs. We confirmed that coincubation of PC12 cells with 30 microM MPP(+) and 100 microM indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP(+) compared with incubation with 30 microM MPP(+) alone. In addition, these NSAIDs markedly reduced the efflux of MPP(+) from PC12 cells. (3-(3-(2-(7-Chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid (MK 571), which is an inhibitor of multidrug resistance proteins (MRPs), mimicked the NSAIDs-induced effects, increasing cell toxicity and promoting the accumulation of MPP(+). Moreover, some types of MRPs' mRNA were detected in PC12 cells. These results suggest that some NSAIDs might cause a significant increase in the intracellular accumulation of MPP(+) via the suppression of reverse transport by the blockade of MRP, resulting in the potentiation of MPP(+)-induced cell death.
authors.affiliation: Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Minamiku, Hiroshima 734-8553, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Kei
authors.initials: K
authors.lastname: Kumagai
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kitayama
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Dohi
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015655:1-Methyl-4-phenylpyridinium