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CELLULAR AND MOLECULAR

Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP⁺)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP⁺ in PC12 Cells

Department of Dental Pharmacology, Division of Integrated Medical Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan (N.M., K.K., K.M., T.D.); and Department of Dental Pharmacology, Field of Functional Physiology, Branch of Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (S.K.)

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 . 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 µM MPP⁺ and 100 µM indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP⁺ compared with incubation with 30 µM 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.

Address correspondence to: Prof. Toshihiro Dohi, Kasumi 1-2-3, Minamiku, Hiroshima 734-8553, Japan. E-mail: todohi{at}hiroshima-u.ac.jp