title: Neuroprotective effect through the cerebral sodium-glucose transporter on the development of ischemic damage in global ischemia.
abstract: Diabetes mellitus and impaired glucose metabolism are the most important risk factors for stroke. We recently demonstrated that cerebral ischemic stress causes hyperglycemia (i.e., post-ischemic hyperglycemia) and may worsen ischemic neuronal damage in a mouse model of focal ischemia. However, the detailed mechanisms are still unknown. The sodium-glucose transporter (SGLT) generates inward currents in the process of transporting glucose into cells, resulting in depolarization and increased excitability, which is well known to be caused by cerebral ischemia. Hence, we focused on the role of SGLT on the development of neuronal damage using a global ischemic model. Male ddY mice were subjected to 30min of bilateral carotid artery occlusion (BCAO). The neuronal damage was estimated by histological analysis using HE staining on day 3 after BCAO. Intraperitoneal (i.p.) administration of phlorizin (a specific and competitive inhibitor of SGLT, 200mg/kg immediately after reperfusion) suppressed the development of post-ischemic hyperglycemia on day 1 after BCAO. In contrast, intracerebroventricular (i.c.v.) administration of phlorizin (40μg/mouse immediately and 6h after reperfusion) had no effect on day 1 after BCAO. Interestingly, the development of ischemic neuronal damage was significantly suppressed by i.p. and i.c.v. administration of phlorizin on day 3 after BCAO. In addition, BCAO-induced spasticity was significantly suppressed by PHZ (40μg/mouse, i.c.v.) from using gait analysis. Our results indicated that cerebral SGLT was involved in the development of ischemic neuronal damage in global ischemia.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nishioka
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010695:Phlorhizin / Q000494:pharmacology*; D051247:Sodium-Glucose Transport Proteins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D051247:Sodium-Glucose Transport Proteins; D010695:Phlorhizin
keywords: Global ischemia; Glucose transporter; Hyperglycemia; Neuroprotection; SGLT