The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential.
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.
Miyashita
Kazutoshi
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Japan.
Itoh
Hiroshi
H
Arai
Hiroshi
H
Suganami
Takayasu
T
Sawada
Naoki
N
Fukunaga
Yasutomo
Y
Sone
Masakatsu
M
Yamahara
Kenichi
K
Yurugi-Kobayashi
Takami
T
Park
Kwijun
K
Oyamada
Naofumi
N
Sawada
Naoya
N
Taura
Daisuke
D
Tsujimoto
Hirokazu
H
Chao
Ting-Hsing
TH
Tamura
Naohisa
N
Mukoyama
Masashi
M
Nakao
Kazuwa
K
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
D018696:Neuroprotective Agents; D010455:Peptides; D017382:Reactive Oxygen Species; D053607:Adrenomedullin