Beta-funaltrexamine inhibits inducible nitric-oxide synthase expression in human astroglial cells.
The inducible isoform of nitric-oxide synthase (iNOS) is involved in neuropathogenesis associated with infection and disease in the brain. Hence, there is considerable interest in the identification of therapeutic interventions to prevent iNOS-mediated pathology. Astroglia are a major site of iNOS expression during neuropathogenesis. To mimic a key component of neuroinflammation, human A172 astroglial cells were exposed in vitro to a cytokine mixture containing interferon gamma, tumor necrosis factor alpha, and interleukin-1beta, resulting in significant iNOS expression. Next, we assessed the effects of the mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on cytokine induced iNOS expression in human astroglia. beta-FNA dose-dependently inhibited iNOS expression. beta-FNA transcriptionally (or pre-transcriptionally) inhibited cytokine-induced iNOS activation as indicated by a significant decrease in NOS2 messenger RNA expression. Further characterization of the novel, anti-inflammatory actions of beta-FNA may provide insights for pharmacologic strategies to treat or prevent brain pathologies associated with neuroinflammation.
Davis
Randall L
RL
Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK 74107, USA. randall.davis@okstate.edu
Buck
Daniel J
DJ
Saffarian
Neda
N
Mohan
Shekher
S
DeSilva
Udaya
U
Fernando
Samodha C
SC
Stevens
Craig W
CW
D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics
D004791:Enzyme Inhibitors; D009271:Naltrexone; C024524:beta-funaltrexamine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II