title: Treadmill exercise ameliorates ischemia-induced brain edema while suppressing Na⁺/H⁺ exchanger 1 expression.
abstract: Exercise may be one of the most effective and sound therapies for stroke; however, the mechanisms underlying the curative effects remain unclear. In this study, the effects of forced treadmill exercise with electric shock on ischemic brain edema were investigated. Wistar rats were subjected to transient (90 min) middle cerebral artery occlusion (tMCAO). Eighty nine rats with substantially large ischemic lesions were evaluated using magnetic resonance imaging (MRI) and were randomly assigned to exercise and non-exercise groups. The rats were forced to run at 4-6m/s for 10 min/day on days 2, 3 and 4. Brain edema was measured on day 5 by MRI, histochemical staining of brain sections and tissue water content determination (n=7, each experiment). Motor function in some rats was examined on day 30 (n=6). Exercise reduced brain edema (P<0.05-0.001, varied by the methods) and ameliorated motor function (P<0.05). The anti-glucocorticoid mifepristone or the anti-mineralocorticoid spironolactone abolished these effects, but orally administered corticosterone mimicked the ameliorating effects of exercise. Exercise prevented the ischemia-induced expression of mRNA encoding aquaporin 4 (AQP4) and Na(+)/H(+) exchangers (NHEs) (n=5 or 7, P<0.01). Microglia and NG2 glia expressed NHE1 in the peri-ischemic region of rat brains and also in mixed glial cultures. Corticosterone at ~10nM reduced NHE1 and AQP4 expression in mixed glial and pure microglial cultures. Dexamethasone and aldosterone at 10nM did not significantly alter NHE1 and AQP4 expression. Exposure to a NHE inhibitor caused shrinkage of microglial cells. These results suggest that the stressful short-period and slow-paced treadmill exercise suppressed NHE1 and AQP4 expression resulting in the amelioration of brain edema at least partly via the moderate increase in plasma corticosterone levels.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Nishioka
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Aono
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Mise
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Choudhury
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Miyanishi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Afsana
authors.initials: A
authors.lastname: Islam
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Center for Advanced Research and Education, Asahikawa Medical University, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan. Electronic address: jtanaka@m.ehime-u.ac.jp.
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology* / Q000534:rehabilitation*; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005081:Exercise Therapy / Q000379:methods*; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008297:Male; D015735:Mifepristone / Q000627:therapeutic use; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D062646:Acid Sensing Ion Channel Blockers; C496032:Aqp4 protein, rat; D051401:Aquaporin 4; D016207:Cytokines; D000451:Mineralocorticoid Receptor Antagonists; D009419:Nerve Tissue Proteins; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D013148:Spironolactone; D015735:Mifepristone; D003345:Corticosterone
keywords: Aquaporin 4; Corticosterone; Edema; Glucocorticoid; Immunohistochemistry; Microglia; Mineralocorticoid; NHE; Stroke