Pharmacological shift of the ambiguous nitric oxide action from neurotoxicity to cyclic GMP-mediated protection.
OBJECTIVE
The effect of intracellular cyclic guanosine monophosphate (GMP) increase on neuronal damage was tested using a newly developed nitric oxide-related injury model of cultured spinal cord neurons.


METHODS
Neuronal damage after 24-hour-exposure to sodium nitroprusside (SNP), a nitric oxide (NO) donor, was evaluated by measuring the activity of released lactate dehydrogenase from injured neurons.


RESULTS
Oxygen radical scavengers had a protective effect, indicating that the neuronal damage, elicited by 10 μM SNP, was largely due to peroxynitrite formation. Alternatively, a strong inhibition of the NO-induced damage could also be achieved by an intracellular cyclic GMP increase resulting from the addition of 100 μM 8-bromo-cyclic GMP. Propentofylline (PPF, 1-100 μM), a xanthine derivative and rather selective phosphodiesterase (PDE) inhibitor, enhanced intracellular cyclic GMP elevation induced by SNP exposure. The neuronal damage induced by 10 μM SNP exposure for 24 hours was almost completely blocked in the presence of 1 μM PPF.


CONCLUSIONS
These results suggest that NO has an ambiguous action, i.e. toxic by favoring the formation of, but protective by intracellular cyclic GMP elevation which can be reinforced by PDE inhibition. Therefore, PDE inhibitors, such as PPF, may be useful therapeutic drugs to limit oxidative neuronal damage in the central nervous system.
Kohgami
Shigeru
S
Ehime University, Japan.
Ogata
Tadanori
T
Morino
Tadao
T
Yamamoto
Haruyasu
H
Schubert
Peter
P
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D020287:In Situ Nick-End Labeling / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000633:toxicity*; D009599:Nitroprusside / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000166:cytology; D014970:Xanthines / Q000494:pharmacology
D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D014970:Xanthines; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C032114:propentofylline; D007770:L-Lactate Dehydrogenase; D006152:Cyclic GMP