Role of protein kinase Cdelta in paraquat-induced glial cell death.
Paraquat (1,1'-dimethyl-4,4'-bipyridinium) is structurally similar to the neurotoxin 1-methyl-4-phenyl-4-phenylpyridium ion (MPP+), the active metabolite of the parkinsonism-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which can induce the parkinsonism property in rodents, nonhuman primates, and human. In contrast to the neurotoxic effects of paraquat, little is known about its effects on glial cells. Here, we examined the mechanisms of paraquat toxicity in glial cells in culture. Paraquat treatment also reduced the viability of C6 glial cells in primary astrocyte cultures, and cell death was mostly apoptotic in nature. PKCdelta played a central role in the paraquat-induced glial cell death: (1) the PKCdelta-specific inhibitor rottlerin blocked paraquat-induced glial cell death; (2) paraquat induced tyrosine and threonine phosphorylation of PKCdelta; and (3) transfection of the dominant-negative mutant of PKCdelta attenuated paraquat toxicity. PKCdelta was also involved in the generation of reactive oxygen species (ROS), which mediated the paraquat toxicity. The nicotinamide adenine dinucleotide phosphate (reduced form) oxidase (NADPH oxidase) inhibitor diphenyleneiodonium blocked the paraquat-induced ROS production and subsequent cell death, indicating the involvement of NADPH oxidase in the cytotoxic action of paraquat in glia. PKCdelta was also important in glial cell death induced by MPP+ but not in that induced by rotenone. Last, Rac1 appeared to antagonize paraquat toxicity in glia. These results indicate a gliotoxic effect of paraquat and an opposing role of PKCdelta and Rac1 in paraquat-induced glial cell death.
Kim
Sangseop
S
Department of Pharmacology, Brain Science and Engineering Institute, CMRI, Kyungpook National University School of Medicine, Daegu, Korea.
Hwang
Jaegyu
J
Lee
Won-Ha
WH
Hwang
Dae Youn
DY
Suk
Kyoungho
K
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D001578:Benzopyrans / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010269:Paraquat / Q000633:toxicity*; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C085746:rottlerin; D051745:Protein Kinase C-delta; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D010269:Paraquat