Sodium influx through cerebral sodium-glucose transporter type 1 exacerbates the development of cerebral ischemic neuronal damage.
We recently reported that cerebral sodium-glucose transporter type 1 (SGLT-1) plays a role in exacerbation of cerebral ischemia. However, the mechanism by which cerebral SGLT-1 acts remains unclear. Here we demonstrated that sodium influx through cerebral SGLT-1 exacerbates cerebral ischemic neuronal damage. SGLT-specific sodium ion influx was induced using α-methyl-D-glucopyranoside (α-MG). Intracellular sodium concentrations in primary cortical neurons were estimated using sodium-binding benzofuran isophthalate fluorescence. SGLT-1 knockdown in primary cortical neurons and mice was achieved using SGLT-1 siRNA. The survival rates of primary cultured cortical neurons were assessed using biochemical assays 1 day after treatment. Middle cerebral artery occlusion (MCAO) was used to generate a focal cerebral ischemic model in SGLT-1 knockdown mice. The change in fasting blood glucose levels, infarction development, and behavioral abnormalities were assessed 1 day after MCAO. Treatment with 200mM α-MG induced a continuous increase in the intracellular sodium concentration, and this increase was normalized after α-MG removal. Neuronal SGLT-1 knockdown had no effect on 100µM H2O2-induced neuronal cell death; however, the knockdown prevented the neuronal cell death induced by 17.5mM glucose and the co-treatment of 100µM H2O2/8.75mM glucose. Neuronal SGLT-1 knockdown also suppressed the cell death induced by α-MG alone and the co-treatment of 100µM H2O2/0.01mM α-MG. Our in vivo results showed that the exacerbation of cerebral ischemic neuronal damage induced by the intracerebroventricular administration of 5.0µg α-MG/mouse was ameliorated in cerebral SGLT-1 knockdown mice. Thus, sodium influx through cerebral SGLT-1 may exacerbate cerebral ischemia-induced neuronal damage.
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Yui
Y
Yamazaki
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Shinichi
S
Harada
Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka 577-8502, Japan.
Tetsuyuki
T
Wada
Department of Life Science, Faculty of Science and Engineering, Kinki University, Kowakae 3-4-1, Higashiosaka 577-8502, Japan.
Teruki
T
Hagiwara
Department of Life Science, Faculty of Science and Engineering, Kinki University, Kowakae 3-4-1, Higashiosaka 577-8502, Japan.
Shigeru
S
Yoshida
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan. Electronic address: stoku@pharm.kobegakuin.ac.jp.
Shogo
S
Tokuyama
D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006943:Hyperglycemia / Q000150:complications; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008757:Methylglucosides / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D051247:Sodium-Glucose Transport Proteins / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D008757:Methylglucosides; D034741:RNA, Small Interfering; C495675:Slc5a1 protein, mouse; C490297:Slc5a4b protein, mouse; D051247:Sodium-Glucose Transport Proteins; D051269:Sodium-Glucose Transporter 1; C027020:methylglucoside; D012964:Sodium
Cerebral ischemia; Hyperglycemia; Neuronal damage; Sodium-glucose transporter