Inflammatory mediator and beta-amyloid (25-35)-induced ceramide generation and iNOS expression are inhibited by vitamin E.
To investigate the putative role of beta-amyloid peptide (A beta) in inducing oxidative stress damage in Alzheimer disease (AD), we studied the effects of proinflammatory cytokines and A beta peptide on the induction of inducible nitric oxide synthase (iNOS). A beta(25-35) upregulated the cytokine (TNF-alpha/IL-1 beta)-induced expression of iNOS and the production of nitric oxide (NO) in astrocytes, which were inhibited by vitamin E. A beta treatment of C6 glial cells (together with LPS and IFN-gamma), in addition to inducing iNOS, enhanced the oxidative stress as measured by increased expression of manganese superoxide dismutase and an increase in 2,7'-dichlorofluorescein diacetate fluorescence. We also observed that LPS, IFN-gamma, and A beta(25-35) treatment led to the activation of the sphingomyelin-ceramide (SM-Cer) cascade with an increase in cellular ceramide. Inhibition of the SM-Cer cascade either by vitamin E treatment or by the neutral sphingomyelinase inhibitor 3-O-methyl sphingomyelin also resulted in alteration of the transcriptional binding activities of C/EBP, NFkappaB, AP-1, and CREB in C6 glial cells. Hence, these findings suggest a role for ceramide in iNOS induction and NO production in Abeta-induced AD pathobiology and provide a possible explanation for the beneficial effects of vitamin E therapy.
Ayasolla
Kamesh
K
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Khan
Mushfiquddin
M
Singh
Avtar K
AK
Singh
Inderjit
I
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005910:Glioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D002518:Ceramides; D005609:Free Radicals; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D013109:Sphingomyelins; D014157:Transcription Factors; D014810:Vitamin E; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat