title: Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia.
abstract: The regulation of post-ischemic hyperglycemia plays an important role in suppressing neuronal damage in therapeutic strategies for cerebral ischemia. We previously reported that the cerebral sodium-glucose transporter (SGLT) was involved in the post-ischemic hyperglycemia-induced exacerbation of cerebral ischemic neuronal damage. Cortical SGLT-1, one of the cerebral SGLT isoforms, is dramatically increased by focal cerebral ischemia. In this study, we focused on the involvement of cerebral SGLT-1 in the development of cerebral ischemic neuronal damage. It was previously reported that activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) increases SGLT-1 expression. Moreover, ischemic stress-induced activation of AMPK exacerbates cerebral ischemic neuronal damage. Therefore, we directly confirmed the relationship between cerebral SGLT-1 and cerebral AMPK activation using in vitro primary culture of mouse cortical neurons. An in vivo mouse model of focal cerebral ischemia was generated using a middle cerebral artery occlusion (MCAO). The development of infarct volume and behavioral abnormalities on day 3 after MCAO were ameliorated in cerebral SGLT-1 knock down mice. Cortical and striatal SGLT-1 expression levels were significantly increased at 12h after MCAO. Immunofluorescence revealed that SGLT-1 and the neuronal nuclear antigen (NeuN) were co-localized in the cortex and striatum of MCAO mice. In the in vitro study, primary cortical neurons were cultured for five days before each treatment with reagents. Concomitant treatment with hydrogen peroxide and glucose induced the elevation of SGLT-1 and phosphorylated AMPK/AMPK ratio, and this elevation was suppressed by compound C, an AMPK inhibitor in primary cortical neurons. Moreover, compound C suppressed neuronal cell death induced by concomitant hydrogen peroxide/glucose treatment in primary cortical neurons. Therefore, we concluded that enhanced cerebral SGLT-1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage. One of the mechanisms of cerebral SGLT-1 up-regulation may be involved in the AMPK activation after cerebral ischemia.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogihara
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Japan. Electronic address: stoku@pharm.kobegakuin.ac.jp.
authors.forename: S
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
chemical_list: C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D055372:AMP-Activated Protein Kinases
keywords: 5′-adenosine monophosphate-activated protein kinase; cerebral ischemia; glucose transporter; hyperglycemia; sodium-glucose transporter type 1