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5-Chloroacetyl-2-amino-1,3-selenazoles attenuate microglial inflammatory responses through NF-kappaB inhibition.

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Department of Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin-Si, Republic of Korea.

    ,

    Source

    European journal of pharmacology 589:1-3 2008 Jul 28 pg 53-7

    MeSH

    Animals
    Animals, Newborn
    Anti-Inflammatory Agents
    Cell Line
    Cells, Cultured
    Cyclooxygenase 2
    Dinoprostone
    Dose-Response Relationship, Drug
    Down-Regulation
    Inflammation Mediators
    Interleukin-1beta
    Lipopolysaccharides
    Mice
    Microglia
    NF-kappa B
    Neuroprotective Agents
    Nitric Oxide
    Nitric Oxide Synthase Type II
    Organoselenium Compounds
    Proto-Oncogene Proteins c-akt
    RNA, Messenger
    Rats
    Reverse Transcriptase Polymerase Chain Reaction
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    18538761

    Citation

    Nam, Kyong Nyon, et al. "5-Chloroacetyl-2-amino-1,3-selenazoles Attenuate Microglial Inflammatory Responses Through NF-kappaB Inhibition." European Journal of Pharmacology, vol. 589, no. 1-3, 2008, pp. 53-7.
    Nam KN, Koketsu M, Lee EH. 5-Chloroacetyl-2-amino-1,3-selenazoles attenuate microglial inflammatory responses through NF-kappaB inhibition. Eur J Pharmacol. 2008;589(1-3):53-7.
    Nam, K. N., Koketsu, M., & Lee, E. H. (2008). 5-Chloroacetyl-2-amino-1,3-selenazoles attenuate microglial inflammatory responses through NF-kappaB inhibition. European Journal of Pharmacology, 589(1-3), pp. 53-7. doi:10.1016/j.ejphar.2008.03.034.
    Nam KN, Koketsu M, Lee EH. 5-Chloroacetyl-2-amino-1,3-selenazoles Attenuate Microglial Inflammatory Responses Through NF-kappaB Inhibition. Eur J Pharmacol. 2008 Jul 28;589(1-3):53-7. PubMed PMID: 18538761.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 5-Chloroacetyl-2-amino-1,3-selenazoles attenuate microglial inflammatory responses through NF-kappaB inhibition. AU - Nam,Kyong Nyon, AU - Koketsu,Mamoru, AU - Lee,Eunjoo H, Y1 - 2008/04/01/ PY - 2007/09/12/received PY - 2008/03/06/revised PY - 2008/03/19/accepted PY - 2008/6/10/pubmed PY - 2008/10/25/medline PY - 2008/6/10/entrez SP - 53 EP - 7 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 589 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18538761/5_Chloroacetyl_2_amino_13_selenazoles_attenuate_microglial_inflammatory_responses_through_NF_kappaB_inhibition_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00372-5 DB - PRIME DP - Unbound Medicine ER -