title: The azetidine derivative, KHG26792 protects against ATP-induced activation of NFAT and MAPK pathways through P2X7 receptor in microglia.
abstract: Azetidine derivatives are of interest for drug development because they may be useful therapeutic agents. However, their mechanisms of action remain to be completely elucidated. Here, we have investigated the effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792) on ATP-induced activation of NFAT and MAPK through P2X7 receptor in the BV-2 mouse microglial cell line. KHG26792 decreased ATP-induced TNF-α release from BV-2 microglia by suppressing, at least partly, P2X7 receptor stimulation. KHG26792 also inhibited the ATP-induced increase in IL-6, PGE2, NO, ROS, CXCL2, and CCL3. ATP induced NFAT activation through P2X7 receptor, with KHG26792 reducing the ATP-induced NFAT activation. KHG26792 inhibited an ATP-induced increase in iNOS protein and ERK phosphorylation. KHG26792 prevented an ATP-induced increase in MMP-9 activity through the P2X7 receptor as a result of degradation of TIMP-1 by cathepsin B. Our data provide mechanistic insights into the role of KHG26792 in the inhibition of TNF-α produced via P2X7 receptor-mediated activation of NFAT and MAPK pathways in ATP-treated BV-2 cells. This study highlights the potential use of KHG26792 as a therapeutic agent for the many diseases of the CNS related to activated microglia.
authors.affiliation: Department of Biomedical Laboratory Science, Konyang University, 158, Gwangeodong-ro, Seo-gu, Daejeon 302-832, South Korea.
authors.forename: Eun-A
authors.initials: EA
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Jiae
authors.initials: J
authors.lastname: Kim
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Hoh-Gyu
authors.initials: HG
authors.lastname: Hahn
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon 200-702, South Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Biomedical Laboratory Science, Konyang University, 158, Gwangeodong-ro, Seo-gu, Daejeon 302-832, South Korea. Electronic address: sjyang@konyang.ac.kr.
authors.forename: Seung-Ju
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, South Korea. Electronic address: swcho@amc.seoul.kr.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Cho
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D058920:Purinergic P2X Receptor Antagonists / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001384:Azetidines; D050778:NFATC Transcription Factors; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; C082735:azetidine; D000255:Adenosine Triphosphate
keywords: ATP; Azetidine derivative; Microglial activation; P2X7 receptor; TNF-α