This Article Full Text Full Text (PDF) All Versions of this Article: 147/4/1642    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miyashita, K. Articles by Nakao, K. Search for Related Content PubMed PubMed Citation Articles by Miyashita, K. Articles by Nakao, K.

The Neuroprotective and Vasculo-Neuro-Regenerative Roles of Adrenomedullin in Ischemic Brain and Its Therapeutic Potential

Department of Medicine and Clinical Science (K.M., H.I., H.A., N.S., Y.F., M.S., K.Y., T.Y.-K., K.P., N.O., N.S., D.T., H.T., N.T., M.M., K.N.), Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; Department of Molecular Medicine and Metabolism (T.S.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan; and Department of Medicine (T.-H.C.), National Cheng-Kung University Medical Center, Tainan, Taiwan 701, Republic of China

Address all correspondence and requests for reprints to: Hiroshi Itoh, M.D., Ph.D., Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine; 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: hiito{at}kuhp.kyoto-u.ac.jp.

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.

This article has been cited by other articles:

				N. Oyamada, M. Sone, K. Miyashita, K. Park, D. Taura, M. Inuzuka, T. Sonoyama, H. Tsujimoto, Y. Fukunaga, N. Tamura, et al. The Role of Mineralocorticoid Receptor Expression in Brain Remodeling after Cerebral Ischemia Endocrinology, August 1, 2008; 149(8): 3764 - 3777. [Abstract] [Full Text] [PDF]

				D. Ribatti, M. T. Conconi, and G. G. Nussdorfer Nonclassic Endogenous Novel Regulators of Angiogenesis Pharmacol. Rev., June 1, 2007; 59(2): 185 - 205. [Abstract] [Full Text] [PDF]

				S. Rubattu, N. Hubner, U. Ganten, A. Evangelista, R. Stanzione, E. D. Angelantonio, R. Plehm, R. Langanki, E. Gianazza, L. Sironi, et al. Reciprocal congenic lines for a major stroke QTL on rat chromosome 1 Physiol Genomics, October 11, 2006; 27(2): 108 - 113. [Abstract] [Full Text] [PDF]