Protective effects of lipopolysaccharide preconditioning against nitric oxide neurotoxicity.
We have characterized lipopolysaccharide (LPS) preconditioning-induced neuroprotective mechanisms against nitric oxide (NO) toxicity. Pretreatment of rat cortical cultures with LPS attenuated neurotoxicity of NO donors, including sodium nitroprusside (SNP) and diethylamine NONOate (NONOate). A transiently increased expression of endothelial nitric oxide synthase (eNOS) accompanied by an increase in NO production was observed during LPS preconditioning. Application of NOS inhibitors including L-N(5)-(1-iminoethyl)-ornithine (L-NIO) and L-nitroarginine methylester (L-NAME) abolished LPS-dependent protection against SNP toxicity. The LPS effect was also blocked by KT5823, an inhibitor of cGMP-dependent protein kinase (PKG). Consistently, application of 8-bromo-cyclic GMP (8-Br-cGMP), a slowly degradable cGMP analogue capable of PKG activation, was neuroprotective. LPS preconditioning resulted in a heightened neuronal expression of Bcl-2 protein that was abolished by L-NAME and KT5823, the respective inhibitors of NOS and PKG. Together, our results reveal the signaling cascade of "LPS --> eNOS --> NO --> cGMP/PKG --> Bcl-2" that might have contributed to the LPS protective effects in cortical neurons.
Huang
Chia-Yen
CY
Institute of Neuroscience, Tzu Chi University, Hualien, Taiwan.
Yang
Hui-I
HI
Chen
Shang-Der
SD
Shaw
Fu-Zen
FZ
Yang
Ding-I
DI
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009410:Nerve Degeneration / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000633:toxicity*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D019253:Proto-Oncogene Proteins c-bcl-2; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP