Prooxidant effects of NGF withdrawal and MEK inhibition in sympathetic neurons.
An increase of mitochondrial-derived reactive oxygen species (ROS) occurs in nerve growth factor (NGF)-deprived sympathetic neurons undergoing apoptotic death. It has been reported that NGF suppresses increased ROS production by the mitochondria in these cells through a mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein (MAP) kinase pathway because NGF withdrawal inactivates this pathway and the MEK inhibitor, PD98059, increases ROS in the presence of NGF. We show here that treating rat sympathetic neurons in cell culture with PD98059 greatly decreased cellular concentrations of reduced glutathione (GSH), a major cellular antioxidant. Therefore, it is likely that this inhibitor induces a cellular prooxidant state in NGF-maintained sympathetic neurons primarily by decreasing GSH concentration rather than by causing increased mitochondrial ROS production. These data suggest that the MEK/MAP kinase signaling pathway regulates cellular GSH concentration.
Rebecca A
RA
Kirkland
James L
JL
Franklin
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005333:Fetus / Q000294:innervation; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D020932:Nerve Growth Factor / Q000172:deficiency*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000032:analysis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000166:cytology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology*
D005419:Flavonoids; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; C059597:monochlorobimane; D020932:Nerve Growth Factor; D003513:Cycloheximide; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000111:Acetylcysteine