5-Chloroacetyl-2-amino-1,3-selenazoles attenuate microglial inflammatory responses through NF-kappaB inhibition.
Microglia are the prime effector cells involved in immune and inflammatory responses in the central nervous system (CNS). In pathological conditions, microglia are activated to restore CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various toxic proinflammatory molecules. Thus, negative regulators of microglial activation have been identified as potential therapeutic candidates in many neurological diseases. A number of selenium-containing compounds show antioxidant activity. In this study, we investigated 2-amino-1,3-selenazole derivatives with regard to anti-inflammatory activity or inhibitory effects on microglial activation. Among 26 derivatives of 2-amino-1,3-selenazole and bis-(2-amino-5-selenazoyl) ketones, we observed that 5-chloroacetyl-2-piperidino-1,3-selenazole (CS1) and 5-chloroacetyl-2-morpholino-1,3-selenazole (CS2) strongly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) release from BV2 microglial cells. In rat primary cultured microglia, CS1 and CS2 significantly reduced LPS-induced production of NO, tumor necrosis factor (TNF)-alpha, and prostaglandin E(2). Real-time reverse transcription-polymerase chain reaction analysis revealed that the pretreatment of primary microglial cells with CS1 and CS2 attenuated LPS-induced mRNA expression for inducible NO synthase, TNF-alpha, interleukin-1beta, and cyclooxygenase-2. In addition, CS1 and CS2 suppressed LPS-induced activation of nuclear factor-kappaB and Akt. These results suggest that CS1 and CS2 may provide neuroprotection by suppressing the proinflammatory pathway in activated microglia.
Department of Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin-Si, Republic of Korea.
Kyong Nyon
KN
Nam
Mamoru
M
Koketsu
Eunjoo H
EH
Lee
D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone