Received for publication September 24, 2008.
Revised October 30, 2008.
Accepted for publication October 30, 2008.

A functional role for sodium dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation

Abstract

In the current study we determined the functional significance of sodium dependent/independent glucose transporters at the neurovasculature during oxygen glucose deprivation (OGD). Confluent brain endothelial cells cocultured with astrocytes were exposed to varying degrees of in vitro stroke conditions. Glucose transporter 1 (GLUT1) and sodium glucose cotransporter (SGLT) activity were investigated by luminal membrane uptake and transport studies using [³H] D-glucose and also by [¹⁴C] alpha methyl D-glucopyranoside (AMG), a specific, nonmetabolized substrate of SGLT. In vivo middle cerebral artery occlusion (MCAO) experiments were tested to determine if blood-brain barrier (BBB) SGLT activity was induced during ischemia. Increases in luminal D-glucose and AMG uptake and transport were observed with in vitro stroke conditions. Specific inhibitor experiments suggest a combined role for both SGLT and GLUT1 at the BBB during OGD. A time dependent increase in the uptake of AMG was also seen in mice exposed to permanent focal ischemia and this increase was sensitive to SGLT inhibitor, phlorizin. Infarct and edema ratio during ischemia were significantly decreased by the inhibition of this transporter. These results show that both GLUT1 and SGLT play a role at the BBB in the blood-to-brain transport of glucose during ischemic conditions and inhibition of SGLT during stroke has the potential to improve stroke outcome. Pharmacological modulation of this novel BBB transporter could prove to be a brain vascular target in stroke.

Key words: Blood-brain barrier, Brain Edema, Focal Ischemia, Glucose transport, Sodium Glucose Cotransporter, Stroke