A novel compound, RS-1178, specifically inhibits neuronal cell death mediated by beta-amyloid-induced macrophage activation in vitro.
beta-Amyloid peptide (Abeta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation in the brain leading to cell loss and cognitive decline. Accumulating evidence shows Abeta activates microglia, which play the role of the brain's immune system, and mediates inflammatory responses in the brain. Thus, a compound inhibiting Abeta-induced activation of microglia may lead to a novel therapy for AD. However, the compound should not inhibit natural immune responses during events such as bacterial infections. We investigated the effect of a synthesized compound, 7,8-dihydro-5-methyl-8-(1-phenylethyl)-6H-pyrrolo [3,2-e] [1,2,4] triazolo [1,5-a] pyrimidine (RS-1178) on macrophage activation induced by various stimulants. The activation of macrophages was determined by nitric oxide or tumor necrosis factor alpha production. RS-1178 inhibited Abeta-induced macrophage activation but did not inhibit zymosan A- nor lipopolysaccharide (LPS)-induced macrophage activation. Moreover, RS-1178 attenuated neurotoxicity due to Abeta-induced macrophage activation in neuron-macrophage co-cultures but not neurotoxicity due to zymosan A- or LPS-induced macrophage activation. In conclusion, RS-1178 showed a specific inhibitory effect on Abeta-induced macrophage activation. Although the exact mechanisms of this effect remain unknown, RS-1178 may provide a novel therapy for AD.
Neuroscience and Immunology Research Laboratories, Sankyo Co. Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. shiegek@shina.sankyo.co.jp
Shigeko
S
Uryu
Shinya
S
Tokuhiro
Takako
T
Murasugi
Tomiichiro
T
Oda
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D052160:Benzothiazoles; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D011743:Pyrimidines; C467691:RS 1178; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C009462:thioflavin T; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D020928:Mitogen-Activated Protein Kinases