The indolocarbazole Gö6976 protects neurons from lipopolysaccharide/interferon-gamma-induced cytotoxicity in murine neuron/glia co-cultures.
The expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) after exposure to endotoxins has been implicated in immune-mediated neurotoxicity. The indolocarbazole compound Gö6976, which has been described as a selective protein kinase C (PKC) inhibitor in vitro, rescued neurons from lipopolysaccharide/interferon-gamma (LPS/IFNgamma)- or interleukin-1alpha/tumor necrosis alpha/IFNgamma (IL-1alpha/TNFalpha/IFNgamma)-induced cytotoxicity in murine primary neuron-glia co-cultures. Other compounds known to inhibit PKC, Ro31-8220, GF109203X, Gö7874, H7, staurosporine and H89, failed to rescue neurons from the LPS/IFNgamma-induced cytotoxicity. These results suggest that the neuroprotection by Gö6976 from the LPS/IFNgamma-induced neuronal cell death is not mediated through its reputed effects on PKC activity. The neuroprotection paralleled the inhibition of iNOS gene expression and NO production. However, further analyses correlating NO production with the extent of neurotoxicity suggested that additional mechanism(s) besides the inhibition of the iNOS/NO system may be responsible for the neuroprotective effects of Gö6976. An understanding of the mechanism underlying the neuroprotective effect of Gö6976 may provide key insights into potential interventions for immune-mediated neurodegenerative diseases.
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.
G H
GH
Jeohn
B
B
Wilson
W C
WC
Wetsel
J S
JS
Hong
D000818:Animals; D000831:Animals, Newborn; D002227:Carbazoles / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology*; D007371:Interferon-gamma / Q000633:toxicity*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000032:analysis; D019006:Neural Cell Adhesion Molecules / Q000032:analysis; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D002227:Carbazoles; D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C081021:Go 6976; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate