title: A Novel Therapeutic Peptide as a Partial Agonist of RANKL in Ischemic Stroke.
abstract: The enhanced receptor activator of nuclear factor-κB (NFκB) ligand (RANKL) and its receptor (RANK) signal have been reported to attenuate ischemic brain injury through inhibition of Toll-like receptor (TLR) 4-mediated inflammation. However, augmentation of the RANKL/RANK signal also accelerates osteoporosis, which is a potential problem in clinical use of RANKL. Therefore, we developed novel peptides, microglial healing peptides (MHPs), which were based on the DE and/or EF loop of RANKL. Among them, MHP1 was the most effective inhibitor of TLR4-induced inflammations in microglia/macrophages. The effects depended on RANK, as confirmed by knockdown experiments. In contrast to RANKL, MHP1 did not stimulate osteoclast differentiation. Unexpectedly, MHP1 inhibited RANKL-induced osteoclast differentiation. These findings suggested that MHP1 was a partial agonist of RANKL, and administration of MHP1 attenuated ischemic injury by decreasing inflammation. MHP1 could be a novel therapeutic agent for treating ischemic stroke.
authors.affiliation: Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Japan.|Postgraduate Medical Training Centre, Osaka University Hospital, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Kurinami
authors.affiliation: Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Japan.|Department of Neurology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.affiliation: Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.affiliation: Department of Nutritional Science, Kansai University of Welfare Sciences, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Health Development and Medicine, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koriyama
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, the University of Tokyo, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Wakayama
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D002545:Brain Ischemia; D002454:Cell Differentiation / Q000187:drug effects; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D053245:RANK Ligand / Q000819:agonists* / Q000378:metabolism; D000067996:RAW 264.7 Cells; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D010455:Peptides; D053245:RANK Ligand; C493487:Tlr4 protein, mouse; C505689:Tnfsf11 protein, mouse; D051197:Toll-Like Receptor 4