Cyclic GMP-dependent pathways protect differentiated oligodendrocytes from multiple types of injury.
The cyclic GMP analog 8-bromo-cyclic GMP (8-Br-cGMP) protects differentiated murine oligodendrocytes (OLs) from caspase-mediated death initiated by staurosporine, thapsigargin or kainate. Caspase-independent death caused by high levels of NO is also partially prevented by 8-Br-cGMP. Inhibitors of protein kinase G (cGMP-dependent protein kinase, cGK) reversed protection, supporting involvement of cGK. Since NO stimulates soluble guanylate cyclase, increasing cGMP, we treated OLs with low levels of NO and observed partial protection against thapsigargin, staurosporine and kainate. Two inhibitors of mitochondrial pore transition (MPT), cyclosporin A and bongkrekic acid, were poorly protective, indicating that cGMP is not acting primarily by blocking MPT. 8Br-cGMP was more effective than 8Br-cAMP in protecting against staurosporine or release of intracellular Ca(++) by thapsigargin. The cAMP analog exhibited little or no protection against kainate or high levels of NO. Thus cGK signaling is more effective than protein kinase A or phosphodiesterase 3 signaling in preventing OL death.
Benjamins
Joyce A
JA
Department of Neurology, Wayne State University School of Medicine, 1228 Elliman Building, 421 E. Canfield Avenue, Detroit, MI 48201, USA. joyce.benjamins@wayne.edu
Nedelkoska
Liljana
L
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001865:Bongkrekic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D009569:Nitric Oxide / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C118603:NOC 12; D009603:Nitroso Compounds; D001865:Bongkrekic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D019284:Thapsigargin; D026423:S-Nitroso-N-Acetylpenicillamine; D016572:Cyclosporine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D019311:Staurosporine; D007608:Kainic Acid