Prolyl hydroxylase inhibitors delay neuronal cell death caused by trophic factor deprivation.

Abstract

Nerve growth factor (NGF) serves a critical survival-promoting function for developing sympathetic neurons. Following removal of NGF, sympathetic neurons undergo apoptosis characterized by the activation of c-Jun N-terminal kinases (JNKs), up-regulation of BH3-only proteins including BcL-2-interacting mediator of cell death (BIM)(EL), release of cytochrome c from mitochondria, and activation of caspases. Here we show that two small-molecule prolyl hydroxylase inhibitors frequently used to activate hypoxia-inducible factor (HIF) - ethyl 3,4-dihydroxybenzoic acid (DHB) and dimethyloxalylglycine (DMOG) - can inhibit apoptosis caused by trophic factor deprivation. Both DHB and DMOG blocked the release of cytochrome c from mitochondria after NGF withdrawal, whereas only DHB blocked c-Jun up-regulation and phosphorylation. DHB, but not DMOG, also attenuated the induction of BIM(EL) in NGF-deprived neurons, suggesting a possible mechanism whereby DHB could inhibit cytochrome c release. DMOG, on the other hand, was substantially more effective at stabilizing HIF-2alpha and inducing expression of the HIF target gene hexokinase 2 than was DHB. Thus, while HIF prolyl hydroxylase inhibitors can delay cell death in NGF-deprived neurons, they do so through distinct mechanisms that, at least in the case of DHB, are partly independent of HIF stabilization.

• Authors: David J Lomb, Jennifer A Straub, Robert S Freeman
• Journal: Journal of neurochemistry (J Neurochem) Vol. 103 Issue 5 Pg. 1897-906 (Dec 2007) ISSN: 1471-4159 [Electronic] England
• PMID: 17760870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acids, Dicarboxylic
• Enzyme Inhibitors
• Hydroxybenzoates
• Proto-Oncogene Proteins c-jun
• ethyl protocatechuate
• Cytochromes c
• Nerve Growth Factor
• Procollagen-Proline Dioxygenase
• oxalylglycine

Topics

• Amino Acids, Dicarboxylic (pharmacology)
• Animals
• Animals, Newborn
• Cell Death (drug effects)
• Cells, Cultured
• Cytochromes c (metabolism)
• Embryo, Mammalian
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (drug effects)
• Hydroxybenzoates (pharmacology)
• Mitochondria (drug effects)
• Nerve Growth Factor (deficiency)
• Neurons (drug effects)
• Procollagen-Proline Dioxygenase (antagonists & inhibitors)
• Proto-Oncogene Proteins c-jun (metabolism)
• Rats
• Superior Cervical Ganglion (cytology)