title: The role of mineralocorticoid receptor expression in brain remodeling after cerebral ischemia.
abstract: Mineralocorticoid receptors (MRs) are classically known to be expressed in the distal collecting duct of the kidney. Recently it was reported that MR is identified in the heart and vasculature. Although MR expression is also found in the brain, it is restricted to the hippocampus and cerebral cortex under normal condition, and the role played by MRs in brain remodeling after cerebral ischemia remains unclear. In the present study, we used the mouse 20-min middle cerebral artery occlusion model to examine the time course of MR expression and activity in the ischemic brain. We found that MR-positive cells remarkably increased in the ischemic striatum, in which MR expression is not observed under normal conditions, during the acute and, especially, subacute phases after stroke and that the majority of MR-expressing cells were astrocytes that migrated to the ischemic core. Treatment with the MR antagonist spironolactone markedly suppressed superoxide production within the infarct area during this period. Quantitative real-time RT-PCR revealed that spironolactone stimulated the expression of neuroprotective or angiogenic factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), whereas immunohistochemical analysis showed astrocytes to be cells expressing bFGF and VEGF. Thereby the incidence of apoptosis was reduced. The up-regulated bFGF and VEGF expression also appeared to promote endogenous angiogenesis and blood flow within the infarct area and to increase the number of neuroblasts migrating toward the ischemic striatum. By these beneficial effects, the infarct volume was significantly reduced in spironolactone-treated mice. Spironolactone may thus provide therapeutic neuroprotective effects in the ischemic brain after stroke.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Oyamada
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Miyashita
authors.forename: Kwijun
authors.initials: K
authors.lastname: Park
authors.forename: Daisuke
authors.initials: D
authors.lastname: Taura
authors.forename: Megumi
authors.initials: M
authors.lastname: Inuzuka
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Sonoyama
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002544:Cerebral Infarction / Q000378:metabolism / Q000503:physiopathology*; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists; D009043:Motor Activity / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology; D013997:Time Factors
chemical_list: D042501:Angiogenic Proteins; D000451:Mineralocorticoid Receptor Antagonists; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone