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 (GLUT) 1 and sodium glucose cotransporter (SGLT) activity were investigated by luminal membrane uptake and transport studies using [3 H]D-glucose and also by [ 14 C]␣-methyl D-glucopyranoside (AMG), a specific, nonmetabolized substrate of SGLT. In vivo middle cerebral artery occlusion experiments were tested to determine whether 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 the 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.

Addition of NMDA-receptor antagonist MK801 during oxygen/glucose deprivation moderately attenuates the upregulation of glucose uptake after subsequent reoxygenation in brain endothelial cells

“…Since strongest effects on glut1 regulation were found after OGD, further investigations were done under OGD conditions. Recently, presence and functional relevance of a second glucose transporter at the BBB, called sglt1, was reported [4,15,23]. Results shown in figure 2 revealed that mRNA of sglt1 was significantly downregulated during six hours of OGD (0.57-fold, p<0.001) compared to according normoxia samples.…”

“…Furthermore, functionality of sglts in BBB models was shown in vitro and an important role for sglts in vivo in edema formation during stroke was suggested [15,23]. However, sglt functionality at the BBB under physiological conditions is under doubt [25].…”

“…Recently, Espinoza-Rojo et al [6] suggested to investigate glucose transporter as novel targets for the treatment of stroke. Since it is known that glucose transporters transport water together with glucose in order to compensate for the osmotic pressure [14,23,24], it was hypothesized that this co-transport of water may contribute to the formation of edema during stroke. Thus, it could be worthy to elucidate the underlying mechanisms leading to the upregulation of glut1 at the BBB.…”

“…Thus, the first aim of the presented work was to investigate our hypothesis that MK801 can reduce the upregulation of glut1 during OGD in brain endothelial cells and to elucidate the contribution of this inhibition onto the total glucose uptake. Recently, presence and upregulation of sodium coupled glucose 4 transporter 1 (sglt1) during OGD was reported in bovine brain endothelial cells [23].…”

Astrocytic transporters in Alzheimer's disease

“…accounts for the majority of glucose entry into CNS tissue through brain vascular endothelial cells, although there is evidence that SGLTs can also contribute to this process (87). The main astrocytic glucose transporter is GLUT1, while neurons, by contrast, express mainly GLUT3 which has a higher transport activity than GLUT1 (88).…”