TY - JOUR T1 - Regulation of Nerve Growth Factor Release by Nitric Oxide through Cyclic GMP Pathway in Cortical Glial Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 339 LP - 347 DO - 10.1124/mol.56.2.339 VL - 56 IS - 2 AU - Huabao Xiong AU - Kiyofumi Yamada AU - Hussam Jourdi AU - Meiko Kawamura AU - Nobuyuki Takei AU - Daiken Han AU - Toshitaka Nabeshima AU - Hiroyuki Nawa Y1 - 1999/08/01 UR - http://molpharm.aspetjournals.org/content/56/2/339.abstract N2 - In the present study, we found thatS-nitroso-N-acetyl-dl-penicillamine, a spontaneous nitric oxide (NO) generator, dose-dependently inhibited basal nerve growth factor (NGF) release from mixed glial cells. To elucidate the function of endogenous NO in the regulation of NGF release, the mixed glial cells were stimulated with lipopolysaccharide (LPS) or LPS plus interferon-γ (IFNγ). The results showed that LPS alone induced NGF release and moderate NO production. However, costimulation with LPS plus IFNγ greatly enhanced NO production but significantly suppressed LPS-induced NGF release. WhenN G-monomethyl-l-arginine, an NOS inhibitor, was added to the culture, the suppression of NGF release by IFNγ was significantly reduced. Quantitative reverse transcription-polymerase chain reaction demonstratedS-nitroso-N-acetyl-dl-penicillamine was also able to inhibit the LPS-induced NGF mRNA expression. To understand the different contributions of astroglia and microglia to this phenomenon, both cell types were purified. We found purified astroglia produced high amounts of NGF but low amounts of NO. However, purified microglia produced a large amount of NO but very low amounts of NGF after stimulation with LPS or LPS plus IFNγ. Our data also indicated the second messenger cyclic GMP, but not cyclic AMP, was able to inhibit basal NGF release. In vivo experiments confirmed that NGF protein level was significantly enhanced in rats treated withl-N ω-nitro-arginine methyl ester and in endothelial NO synthase mutant mice. Taken together, we conclude NO derived mainly from microglia down-regulates NGF release from astroglia at the transcriptional level by stimulating cyclic GMP pathway. ER -