Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 14 No. 4 • September 2011


The Brain Glucose Transporter GLUT-1 Also Transports Dehydroascorbic Acid Into the Brain Where It is Reduced To Ascorbic Acid

An early paper1 reporting on the transport of glucose into the brain found that the tight interendothelial cell junctions of the blood-brain barrier prevent the entry into the brain of water-soluble substances such as glucose. So how does the brain, highly dependent upon glucose as a fuel for energy production, get its glucose? Answer: Glucose is actively transported across the blood-brain barrier by a transporter similar to the one that delivers glucose to erythrocytes (red blood cells).1b “It has been shown that essentially 100% of glucose transporter binding sites at the blood-brain barrier can be accounted for by the GLUT-1 [glucose transporter 1] isoform; and that the GLUT-1 gene is expressed selectively in microvascular endothelium in the brain with minimal, if any, expression of this gene in neurons in vivo.”2

Interestingly, GLUT-1 not only transports glucose into the brain, but also delivers dehydroascorbic acid (the oxidized form of vitamin C) across the blood-brain barrier into the brain, where it is rapidly reduced to ascorbate.3 “Recent evidence indicates that dehydroascorbic acid crosses the blood-brain barrier via GLUT1 and is rapidly reduced to ascorbate and thus trapped within the brain. This trapping mechanism may contribute to the high vitamin C levels in the brain without the participation of an active transport mechanism.”3

GLUT-1 Expression Decreased in Aged Rats But Increased in Aged Rats by Alpha Lipoic Acid

In another paper,4 it was reported that there is an age-related decrease in GLUT-1 expression in rats in studies comparing the GLUT-1 induced uptake of glucose by leukocytes (white blood cells) in aged compared to young rats. This is thought to be a contributing factor to age-related decline of phagocytic immune function.4 Data4 also showed that administration of alpha lipoic acid to aged rats for 14 days caused an increase in the expression of GLUT-1 when compared to aged control rats (which had a decreased expression of GLUT-1 compared to young rats).

Another paper5 reports that there is an age-associated decline in ascorbic acid concentration, recycling (recycling of ascorbic acid from dehydroascorbic acid) and biosynthesis in rat hepatocytes (liver cells). In this paper, the authors found that that (R)-alpha-lipoic acid almost completely reversed the age-associated decline in ascorbic acid concentration (including decreased recycling of dehydroascorbic acid to ascorbic acid) in the rat hepatocytes. Another paper6 reports further on the role of alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria.

A paper2 reporting on a congenital condition in which GLUT-1 deficiency in humans exists, resulting in low levels of glucose in the cerebrospinal fluid as well as impaired transport of dehydroascorbic acid notes: “It has been suggested that in tissues dependent on GLUT-1 for glucose transport the antioxidant thioctic acid [also called alpha lipoic acid] may be of benefit, as it can translocate GLUT-1 from intracellular pools to the plasma membrane in response to insulin; and benefit has been reported.”

In the earlier paper1 mentioned above, the authors explained that an explanation for the relatively high density of the glucose transporter protein in brain microvessels is that brain microvessels constitute less than 1% of the brain’s weight, yet must transport all the glucose needed for oxidative metabolism of the whole brain. Thus, “the density of the glucose transporter moiety in brain capillaries is 10 to 20 times higher than the density of the transporter in membranes of other mammalian tissues such as adipocytes [fat cells] and myocytes [muscle cells].”1 GLUT-1 is reduced in specific regions of the brain, including the hippocampus, during normal aging. Thus, preventing age-associated reduction in GLUT-1 expression may help prevent the burden of age-associated reduced energy and antioxidant supplies.

Finally, another recent paper7 reports on the regulation of glucose transporters in the ischemic brain (resulting from stroke and other forms of occlusion of blood vessels delivering nutrients to the brain). As the paper reports, “... glucose transport becomes the limiting step [in brain metabolism] in certain steps, such as cerebral ischemia, in which brain glucose fluctuations are primarily associated with blood brain barrier (BBB) permeability and subsequently with GLUT transcriptional and translational expression changes.”

In this paper7 the authors review recent papers on the neuroprotective potential of GLUT upregulation in ischemic stroke, where evidence suggests neuroprotective effects of augmented GLUTs. They note that the upregulation of GLUTs takes place naturally as a result of cerebral ischemia as a protective response. Some natural substances have been associated with this GLUT upregulation. For example, they report that one study found that VITAMIN E (400–600 μg/day) given freely in drinking water for one week before middle carotid artery occlusion-induced ischemia and for an additional 5 weeks after occlusion reduced the brain infarct volume (brain cells killed by the ischemia) by about 50% and reduced the space navigation disability in rats. Induced expression of GLUT3 mRNA and protein expression was reported.

Aged Garlic Extract

Treatment with aged garlic extract before the onset of ischemia has been shown to be beneficial in counteracting cerebral damage.7 Recently, the authors7 evaluated the effect of aged garlic extract on GLUT1 and GLUT3 mRNA expression in rats subjected to middle carotid artery occlusion for 2 hours. “We observed that GLUT1 (2.43 ± 0.77 fold) and GLUT3 (3.16 ± 0.48 fold) increase after 1 hour and return to basal level after 2 hours of reperfusion.” They also report two other studies in which VITAMIN E or QUERCETIN were shown to induce an increase in GLUT expression.

Finally, the paper7 also reported work in which other researchers found that ESTRADIOL pretreatment reduced the ischemic damage (by greater than 50%) following middle carotid artery occlusion in rat. “In the penumbral ischemic region, where cortical tissues are supplied primarily by the anterior cerebral artery but also, to small extent, by the middle cerebral artery, E2 [17-beta estradiol] treatment caused an increase in GLUT1 protein (23.3%) compared with GLUT1 at the lesion side of OVX [ovariectomized] rats.”7

“... glucose transport activity is probably one of the most important mechanisms for the enhanced hypoxic tolerance induced by hypoxic preconditioning. Yu et al demonstrated that preconditioned neuronal and astroglial hippocampal cultures showed an increase in GLUT expression.”7

References

1. Kalaria et al. The glucose transporter of the human brain and blood-brain barrier. Ann Neuro 24:757-64 (1988).
1b. Montel-Hagen et al. Erythocyte GLUT1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. Cell 132:1039-48 (2008).
2. Gordon and Newton. Glucose transporter type 1 (GLUT-1) deficiency. Brain Dev 27:477-80 (2003).
3. Klepper et al. Deficient transport of dehydroascorbic acid in the glucose transporter protein syndrome. Ann Neurol 44:286-7 (1998).
4. Palaniyappan and Alphonse. Immunomodulatory effect of DL-alpha-lipoic acid in aged rats. Exp Gerontol 46:709- 15 (2011).
5. Lykkesfeldt et al. Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes—reversal with (R)-alpha-lipoic acid supplementation. FASEB J 12:1183-9 (1998).
6. Xu and Wells. Alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria. J Bioenerg Biomembr 28(1):77-85 (1996).
7. Espinoza-Rojo et al. Glucose transporters regulation on ischemic brain: possible role as therapeutic target. Cent Nerv Syst Agents Med Chem 10:317-325 (2010).

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