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

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 upregulation 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. Keywords: Cerebral ischemia, glucose transporter, neuroprotection, glutamate-induced excitotoxicity, hypoxia, glucose deprivation, excitotoxicity, oxidative stress, inflammation, Glucose transport activity, hexokinase, glycolysis, penumbra, neurological dysfunction, endothelial cell, interstitium, two hypoxia response elements (HRE), cAMP-response elementbinding protein (CREB), middle carotid artery occlusion (MCAO), proportionate, metabotropic glutamate receptors, AMP-activated protein kinase (AMPK), GLUT isoforms, dentate gyrus, astroglia, brain endothelium, adenylate-uridylate-rich elements (ARE), cytoplasmic deadenylation, Vitamin E, tocopherols, nitric oxide (NO), Aged Garlic Extract (AGE), S-allylcysteine (SAC), organosulfur, thromboembolism, ovariectomized (OVX), astroglial hippocampal, cytochalasin B