title: The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential.
abstract: Adrenomedullin (AM) is a vasodilating hormone secreted mainly from vascular wall, and its expression is markedly enhanced after stroke. We have revealed that AM promotes not only vasodilation but also vascular regeneration. In this study, we focused on the roles of AM in the ischemic brain and examined its therapeutic potential. We developed novel AM-transgenic (AM-Tg) mice that overproduce AM in the liver and performed middle cerebral artery occlusion for 20 min (20m-MCAO) to examine the effects of AM on degenerative or regenerative processes in ischemic brain. The infarct area and gliosis after 20m-MCAO was reduced in AM-Tg mice in association with suppression of leukocyte infiltration, oxidative stress, and apoptosis in the ischemic core. In addition, vascular regeneration and subsequent neurogenesis were enhanced in AM-Tg mice, preceded by increase in mobilization of CD34(+) mononuclear cells, which can differentiate into endothelial cells. The vasculo-neuro-regenerative actions observed in AM-Tg mice in combination with neuroprotection resulted in improved recovery of motor function. Brain edema was also significantly reduced in AM-Tg mice via suppression of vascular permeability. In vitro, AM exerted direct antiapoptotic and neurogenic actions on neuronal cells. Exogenous administration of AM in mice after 20m-MCAO also reduced the infarct area, and promoted vascular regeneration and functional recovery. In summary, this study suggests the neuroprotective and vasculo-neuro-regenerative roles of AM and provides basis for a new strategy to rescue ischemic brain through its multiple hormonal actions.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arai
authors.forename: Takayasu
authors.initials: T
authors.lastname: Suganami
authors.forename: Naoki
authors.initials: N
authors.lastname: Sawada
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yamahara
authors.forename: Takami
authors.initials: T
authors.lastname: Yurugi-Kobayashi
authors.forename: Kwijun
authors.initials: K
authors.lastname: Park
authors.forename: Naofumi
authors.initials: N
authors.lastname: Oyamada
authors.forename: Naoya
authors.initials: N
authors.lastname: Sawada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Taura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Ting-Hsing
authors.initials: TH
authors.lastname: Chao
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D002545:Brain Ischemia / Q000628:therapy*; D002544:Cerebral Infarction / Q000628:therapy; D003342:Corpus Striatum / Q000098:blood supply; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009416:Nerve Regeneration; D018696:Neuroprotective Agents; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D017382:Reactive Oxygen Species
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; D017382:Reactive Oxygen Species; D053607:Adrenomedullin