Role of protein kinase Cδ in paraquat-induced glial cell death

• Published in: Journal of neuroscience research Vol. 86; no. 9; pp. 2062 - 2070
• Main Authors: Kim, Sangseop, Hwang, Jaegyu, Lee, Won-Ha, Hwang, Dae Youn, Suk, Kyoungho
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2008
• Subjects: apoptosis; astrocytes; glia; NADPH oxidase; paraquat; Parkinson's diseases; PKC; ROS
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.21643

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. PKCδ played a central role in the paraquat‐induced glial cell death: (1) the PKCδ‐specific inhibitor rottlerin blocked paraquat‐induced glial cell death; (2) paraquat induced tyrosine and threonine phosphorylation of PKCδ; and (3) transfection of the dominant‐negative mutant of PKCδ attenuated paraquat toxicity. PKCδ 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. PKCδ 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 PKCδ and Rac1 in paraquat‐induced glial cell death. © 2008 Wiley‐Liss, Inc.