Neuroprotective effect of cyclic GMP against radical-induced toxicity in cultured spinal motor neurons.
We have previously reported that nitric oxide-related cyclic guanosine-3',5'-monophosphate (GMP) protected spinal nonmotor neurons, but not motor neurons against chronic glutamate-induced toxicity, which is associated with selective motor neuronal death after glutamate stress. In this report, we investigated the effect of cyclic GMP against reactive oxygen species (ROS)-induced toxicity in cultured neurons from embryonic rat spinal cords. Pretreatment with a cGMP analogue, 8-bromoguanosine monophosphate (8br-cGMP), for 12-24 hours protected both spinal motor neurons and nonmotor neurons against injury induced by either hydrogen peroxide (H(2)O(2)), or a glutathione depletor, L-buthionine-[S,R]-sulfoximine (BSO). This protective effect was reversed by coadministration with the cGMP-dependent protein kinase (PKG) inhibitor Arg-Lys-Arg-Ala-Arg-Lys-Glu. Interestingly, when cultures were exposed to BSO for 24 hours to allow irreversible inhibition of glutathione synthesis, 8br-cGMP protected only nonmotor neurons. Our results indicate that cGMP attenuates oxidative injury to cultured spinal neurons, in a mechanism associated with glutathione synthesis.
Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyoku, Kyoto, Japan.
M
M
Urushitani
R
R
Inoue
T
T
Nakamizo
H
H
Sawada
H
H
Shibasaki
S
S
Shimohama
D000818:Animals; D019328:Buthionine Sulfoximine / Q000009:adverse effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000009:adverse effects; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects*; D016877:Oxidants / Q000009:adverse effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects*
D004791:Enzyme Inhibitors; D016877:Oxidants; D017382:Reactive Oxygen Species; C016276:8-bromocyclic GMP; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP