Intracellular zinc release and ERK phosphorylation are required upstream of 12-lipoxygenase activation in peroxynitrite toxicity to mature rat oligodendrocytes.
Peroxynitrite toxicity has been implicated in the pathogenesis of white matter injury. The mechanisms of peroxynitrite toxicity to oligodendrocytes (OLs), the major cell type of the white matter, are unknown. Using primary cultures of mature OLs that express myelin basic protein, we found that 3-morpholinosydnonimine, a peroxynitrite generator, caused toxicity to OLs. N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine, a zinc chelator, completely blocked peroxynitrite-induced toxicity. Use of FluoZin-3, a specific fluorescence zinc indicator, demonstrated the liberation of zinc from intracellular stores by peroxynitrite. Peroxynitrite caused the sequential activation of extracellular signal-regulated kinase 42/44 (ERK42/44), 12-lipoxygenase, and generation of reactive oxygen species, which were all dependent upon the intracellular release of zinc. The same cell death pathway was also activated when exogenous zinc was used. These results suggest that in addition to preventing the formation of peroxynitrite, useful strategies in preventing disease progression in pathologies in which peroxynitrite toxicity plays a critical role might include maintaining intracellular zinc homeostasis, blocking phosphorylation of ERK42/44, inhibiting activation of 12-lipoxygenase, and eliminating the accumulation of reactive oxygen species.
Zhang
Yumin
Y
Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, Mass 02115, USA.
Wang
Hong
H
Li
Jianrong
J
Dong
Ling
L
Xu
Ping
P
Chen
Weizhi
W
Neve
Rachael L
RL
Volpe
Joseph J
JJ
Rosenberg
Paul A
PA
D000818:Animals; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016923:Cell Death; D018450:Disease Progression; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006706:Homeostasis; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009836:Oligodendroglia; D030421:Peroxynitrous Acid / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D015032:Zinc / Q000493:pharmacokinetics*
D004676:Myelin Basic Protein; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D001092:Arachidonate 12-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases; D015032:Zinc