Agmatine suppresses nitric oxide production in microglia.
We investigated the effect of agmatine, an arginine metabolite synthesized in the brain, in cultured microglia obtained from neonatal rat cerebral cortex. Agmatine (1-300 microM) did not affect viability of cultured microglia. Activation of microglia by lipopolysaccharide (LPS, 1 microg/ml) caused the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) assessed as the accumulation of nitrite in the culture supernatants. Agmatine had no effect on the expression of iNOS, but significantly suppressed the LPS-induced NO production in a concentration-dependent manner. Agmatine was also effective in suppressing the production of NO induced by a combination of interferon-gamma (500 U/ml) and amyloid beta protein (10 microM). In co-cultures of rat cortical neurons and microglia, LPS caused significant loss of neuron viability. The LPS neurotoxicity was not observed in the absence of microglia, and was completely blocked by the NOS inhibitor diphenyleneiodoium chloride. The neuronal death induced by microglia-derived NO was significantly attenuated by the presence of agmatine. These results suggest that agmatine works to protect neurons by inhibiting the production of NO in microglia.
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, The University of Tokyo, 113-0033, Tokyo, Japan. abe@hoshi.ac.jp
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D000376:Agmatine / Q000378:metabolism* / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D009861:Onium Compounds / Q000494:pharmacology; D051381:Rats
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009861:Onium Compounds; D009569:Nitric Oxide; C007517:diphenyleneiodonium; D000376:Agmatine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat