Sodium transport through the cerebral sodium-glucose transporter exacerbates neuron damage during cerebral ischaemia

• Published in: Journal of pharmacy and pharmacology 2016-07, Vol.68 (7), p.922-931
• Main Authors: Yamazaki, Yui, Harada, Shinichi, Wada, Tetsuyuki, Yoshida, Shigeru, Tokuyama, Shogo
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cell Death - drug effects; Cell Survival - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; cerebral ischaemia; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose; Glucose - antagonists & inhibitors; Glucose - pharmacology; Hydrogen Peroxide - adverse effects; Hydrogen Peroxide - antagonists & inhibitors; hyperglycaemia; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Infusions, Intraventricular; Methylglucosides - administration & dosage; Methylglucosides - antagonists & inhibitors; Methylglucosides - pharmacology; Mice; Neurons - metabolism; Neurons - pathology; Phlorhizin - administration & dosage; Phlorhizin - pharmacology; Primary Cell Culture; Sodium - metabolism; sodium influx; sodium-glucose transporter; Sodium-Glucose Transporter 1 - metabolism; α-methyl-d-glucopyranoside
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12571

Objectives We recently demonstrated that the cerebral sodium‐glucose transporter (SGLT) is involved in postischaemic hyperglycaemia‐induced exacerbation of cerebral ischaemia. However, the associated SGLT‐mediated mechanisms remain unclear. Thus, we examined the involvement of cerebral SGLT‐induced excessive sodium ion influx in the development of cerebral ischaemic neuronal damage. Methods [Na+]i was estimated according to sodium‐binding benzofuran isophthalate fluorescence. In the in vitro study, primary cortical neurons were prepared from fetuses of ddY mice. Primary cortical neurons were cultured for 5 days before each treatment with reagents, and these survival rates were assessed using biochemical assays. In in vivo study, a mouse model of focal ischaemia was generated using middle cerebral artery occlusion (MCAO). Key findings In these experiments, treatment with high concentrations of glucose induced increment in [Na+]i, and this phenomenon was suppressed by the SGLT‐specific inhibitor phlorizin. SGLT‐specific sodium ion influx was induced using a‐methyl‐D‐glucopyranoside (a‐MG) treatments, which led to significant concentration‐dependent declines in neuronal survival rates and exacerbated hydrogen peroxide‐induced neuronal cell death. Moreover, phlorizin ameliorated these effects. Finally, intracerebroventricular administration of a‐MG exacerbated the development of neuronal damage induced by MCAO, and these effects were ameliorated by the administration of phlorizin. Conclusions Hence, excessive influx of sodium ions into neuronal cells through cerebral SGLT may exacerbate the development of cerebral ischaemic neuronal damage.