The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential

Kazutoshi Miyashita, Hiroshi Itoh, Hiroshi Arai, Takayasu Suganami, Naoki Sawada, Yasutomo Fukunaga, Masakatsu Sone, Kenichi Yamahara, Takami Yurugi-Kobayashi, Kwijun Park, Naofumi Oyamada, Naoya Sawada, Daisuke Taura, Hirokazu Tsujimoto, Ting Hsing Chao, Naohisa Tamura, Masashi Mukoyama, Kazuwa Nakao

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1642-1653
Number of pages12
JournalEndocrinology
Volume147
Issue number4
DOIs
Publication statusPublished - 2006 Apr
Externally publishedYes

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Adrenomedullin
Brain
Blood Vessels
Therapeutics
Regeneration
Gliosis
Middle Cerebral Artery Infarction
Neurogenesis
Recovery of Function
Brain Edema
Capillary Permeability
Vasodilation
Transgenic Mice

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. / Miyashita, Kazutoshi; Itoh, Hiroshi; Arai, Hiroshi; Suganami, Takayasu; Sawada, Naoki; Fukunaga, Yasutomo; Sone, Masakatsu; Yamahara, Kenichi; Yurugi-Kobayashi, Takami; Park, Kwijun; Oyamada, Naofumi; Sawada, Naoya; Taura, Daisuke; Tsujimoto, Hirokazu; Chao, Ting Hsing; Tamura, Naohisa; Mukoyama, Masashi; Nakao, Kazuwa.

In: Endocrinology, Vol. 147, No. 4, 04.2006, p. 1642-1653.

Research output: Contribution to journalArticle

Miyashita, K, Itoh, H, Arai, H, Suganami, T, Sawada, N, Fukunaga, Y, Sone, M, Yamahara, K, Yurugi-Kobayashi, T, Park, K, Oyamada, N, Sawada, N, Taura, D, Tsujimoto, H, Chao, TH, Tamura, N, Mukoyama, M & Nakao, K 2006, 'The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential', Endocrinology, vol. 147, no. 4, pp. 1642-1653. https://doi.org/10.1210/en.2005-1038
Miyashita, Kazutoshi ; Itoh, Hiroshi ; Arai, Hiroshi ; Suganami, Takayasu ; Sawada, Naoki ; Fukunaga, Yasutomo ; Sone, Masakatsu ; Yamahara, Kenichi ; Yurugi-Kobayashi, Takami ; Park, Kwijun ; Oyamada, Naofumi ; Sawada, Naoya ; Taura, Daisuke ; Tsujimoto, Hirokazu ; Chao, Ting Hsing ; Tamura, Naohisa ; Mukoyama, Masashi ; Nakao, Kazuwa. / The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential. In: Endocrinology. 2006 ; Vol. 147, No. 4. pp. 1642-1653.
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T1 - The neuroprotective and vasculo-neuro-regenerative roles of adrenomedullin in ischemic brain and its therapeutic potential

AU - Miyashita, Kazutoshi

AU - Itoh, Hiroshi

AU - Arai, Hiroshi

AU - Suganami, Takayasu

AU - Sawada, Naoki

AU - Fukunaga, Yasutomo

AU - Sone, Masakatsu

AU - Yamahara, Kenichi

AU - Yurugi-Kobayashi, Takami

AU - Park, Kwijun

AU - Oyamada, Naofumi

AU - Sawada, Naoya

AU - Taura, Daisuke

AU - Tsujimoto, Hirokazu

AU - Chao, Ting Hsing

AU - Tamura, Naohisa

AU - Mukoyama, Masashi

AU - Nakao, Kazuwa

PY - 2006/4

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N2 - 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.

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