Glucose Transporters Regulation on Ischemic Brain: Possible Role as Therapeutic Target

Abstract

Ischemic stroke is a major cause of death worldwide that provokes a high society cost. Deprivation of blood supply, with the subsequent deficiency of glucose and oxygen, triggers an important number of mechanisms (e.g. excitotoxicity, oxidative stress and inflammation) leading to irreversible neuronal injury. Consequently, ischemia increases the energy demand which is associated with profound changes in brain energy metabolism. Glucose transport activity may adapt to ensure the delivery of glucose to maintain normal cellular function, even at the low glucose levels observed in plasma during ischemia. In the brain, the main glucose transporters (GLUTs) are GLUT3 in neurons and GLUT1 in the microvascular endothelial cells of the blood brain barrier and glia. The intracellular signaling pathways involved in GLUT regulation in cerebral ischemia remain unclear; however, it has been established that ischemia induces changes in their expression. In this review, we describe the effect of glutamate-induced excitotoxicity, mitochondrial damage, glucose deprivation, and hypoxia on GLUTs expression in the brain. Additionally, we discuss the possible role of GLUTs as therapeutic target for ischemia. Despite of the intense research, current therapeutics options for stroke are very limited, therefore it is especially important to find new options. Few studies have examined the neuroprotective potential of GLUT up-regulation in ischemic stroke; however, evidence suggests that augmented GLUTs could be related to a protective mechanism. Increased understanding of the beneficial effects of GLUTs activation provides the rationale for targeting GLUT in the development of new therapeutic strategies.

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

“…and sglt1 in cerebENDs after OGD and reoxygenation on the protein level (see supplementary figure 1) supporting our glucose uptake results and confirming data from the literature that glucose transporters are posttranscriptionally regulated by processes which can control mRNA stability, transporter concentrations at the luminal surface and their affinities to glucose [6,21]. Furthermore, presence and function of other glucose transporters at the BBB should not be neglected.…”

“…Hypoxia leads to an increase of the intracellular Ca-level by influx of extracellular Ca-ions as well as by a Ca-release from intracellular stores at the BBB in vitro, and Casignalling under hypoxia plays a crucial role for the formation of ROS [12]. Then, ROS damage membranes of mitochondria impairing oxidative phosphorylation which result in the upregulation of glucose transporters [6]. Under hypoxia astrocytes play an important role in these processes since they release glutamate to e.g.…”

“…The therapeutical approaches for stroke are limited. 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.…”

“…Glutamate excitotoxicity and OGD can result in the formation of reactive oxygen species (ROS). ROS can cause mitochondrial damage [6]. In this context, it was recently reported that NMDAR inhibitor MK801 was able to block the upregulation of ROS formation and the following disruption of the barrier's integrity after hypoxia or glutamate stimuli in in vitro BBB models [11,12].…”

Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases

“…The upregulation of cerebral GLUT1 (and GLUT3) is considered as a potential preventative neuroprotive therapy for ischemia [253]. Because hyperglycemia is an indicator of severe stroke and this promotes further ischemia in the brain, cerebral GLUTs are also considered as a therapeutic target for post ischemic stroke treatments [254].…”