Nitric oxide-enhanced excitotoxicity-independent apoptosis of glucose-deprived neurons.
Glucose deprivation has been shown to elicit neuronal death via extracellular glutamate accumulation. Here we report that immunostimulated glial expression of inducible nitric oxide synthase enhances the apoptotic death of glucose-deprived cerebellar granule cells (CGC) via the excitotoxicity-independent pathway. CGC cultures were immunostimulated by interferon-gamma (100 U/ml) and lipopolysaccharides (1 microg/ml) and 2 days later were challenged by glucose deprivation. Neither a 2-h Glucose deprivation nor a 2-day immunostimulation altered the viability of CGC. A 2-day immunostimulation, however, markedly enhanced the apoptotic death of CGC glucose-deprived for 1 h. The increased apoptotic death of glucose-deprived CGC after immunostimulation was mimicked by the nitric oxide (NO) releasing reagent 3-morpholinosydnonimine (200 microM, 30 min) and was partially prevented by the NO synthase (NOS) inhibitor N(G)-nitroarginine. The enhanced apoptotic death was not blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists D-2-amino-5-phosphovalerate (APV) and dizocilpine (MK-801) or the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moreover, the NO-induced enhanced apoptotic death occurred without a significant increase of the concentration of glutamate in the bathing medium. Our data indicate that immunostimulated glial cells potentiate the apoptotic death of glucose-deprived CGC in part through the expression of inducible NOS but not through NMDA receptor activation. Potentiation of glucose-deprived CGC death by immunostimulated glial cells may be clinically implicated in the tendency of recurrent ischemic insults to be more severe and fatal than an initial ischemic insult.
Kim
W K
WK
Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, South Korea. won_k@mm.ewha.ac.kr
Chung
J H
JH
Kim
H C
HC
Ko
K H
KH
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005947:Glucose / Q000008:administration & dosage / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D011500:Protein Synthesis Inhibitors; D009569:Nitric Oxide; D018698:Glutamic Acid; D007371:Interferon-gamma; D003513:Cycloheximide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005947:Glucose