Ascorbic acid (vitamin C) is synthesized in rodent liver, circulates in the blood, and is concentrated in the brain. Experiments were performed to characterize the mechanism of ascorbate uptake by rat cerebral astrocytes in primary culture. Astroglial uptake of L-[14C]ascorbate was observed to be both saturable and stereoselective. In addition, uptake was dependent on both the incubation temperature and the concentration of Na+ because it was largely inhibited by cooling to 4 degrees C, by treatment with ouabain to increase intracellular Na+, and by the substitution of K+, Li+, or N-methyl-D-glucamine for extracellular Na+. The affinity for ascorbate was relatively high in cells incubated with a physiological concentration of extracellular Na+, because the apparent Km was 32 microM in 138 mM Na+. However, the affinity for ascorbate was significantly decreased when the extracellular Na+ concentration was lowered. Treatment of astrocytes with dibutyryl cyclic AMP induced stellation and increased the maximum rate of ascorbate uptake by 53%. We conclude that astrocytes possess a stereoselective, high-affinity, and Na+-dependent uptake system for ascorbate. This system may regulate the cerebral ascorbate concentration and consequently modulate neuronal function.

Ascorbic acid uptake by a high-affinity sodium-dependent mechanism in cultured rat astrocytes.

Free radicals seem to be involved in the development of cerebral white matter damage after asphyxia in the premature infant. The immature brain may be at increased risk of free radical mediated injury, as particularly the preterm infant has a relative deficiency in brain antioxidants systems, such as superoxide dismutase and glutathione peroxidase. In vitro studies show that immature oligodendrocytes express an intrinsic vulnerability to reactive oxygen species and free radical scavengers are able to protect immature oligodendrocytes from injury. The aim of this study was to examine the formation of ascorbyl radicals as a marker of oxidative stress in the preterm brain in association with cerebral white matter injury after intrauterine asphyxia. Fetal sheep at 0.65 gestation were chronically instrumented with vascular catheters and an occluder cuff around the umbilical cord. A microdialysis probe was placed in the periventricular white matter. Fetal asphyxia was induced by occlusion of the umbilical cord for 25 min (n = 10). Microdialysis samples were collected for 72 h and analyzed for ascorbyl radicals using electron spin resonance. Five instrumented fetuses served as controls. Three days after the insult, fetal brains were examined for morphologic injury. Umbilical cord occlusion resulted in prolonged and marked increase in ascorbyl radical production in the brain in connection with white matter injury, with activation of microglia cells in periventricular white matter and axonal injury. These data suggest that reperfusion injury following asphyxia in the immature brain is associated with marked free radical production.

/pdf/white-matter-injury-following-prolonged-free-radical-2xh4ec71kg.pdf

White matter injury following prolonged free radical formation in the 0.65 gestation fetal sheep brain.

The nitric oxide/ascorbate cycle: How neurones may control their own oxygen supply

Osteoblasts possess a concentrative L-ascorbate (vitamin C) uptake mechanism involving a Na(+)-dependent ascorbate transporter located in the plasma membrane. The transporter is specific for ascorbate and stereoselective for L-ascorbate over D-isoascorbate. The present study examined the effects of ascorbate supplementation and deprivation on the activity of this transport system. L-ascorbate transport activity was determined by measuring uptake of the vitamin by ROS 17/2.8 osteosarcoma cells during 1 minute incubations with 5 microM L-[14C]ascorbate. The initial rate of L-[14C]ascorbate uptake by ROS 17/2.8 cells grown for 18 h in L-ascorbate-replete medium was 89 +/- 8 nmol/g protein per minute. Following removal of L-ascorbate from the growth medium, the initial rate of uptake increased within 6 h to 126 +/- 13 nmol/g protein per minute. Conversely, the initial rate of uptake by cells grown in ascorbate-free medium decreased following the addition of L-ascorbate, but not D-isoascorbate, to the medium. The effect of ascorbate pretreatment was specific for ascorbate transport in that preincubation of cultures with L-ascorbate did not affect uptake of 2-deoxy-D-glucose. Kinetic analysis revealed that modulation of ascorbate transport arose from changes in the apparent maximum rate of transport (Vmax) without changes in the affinity of the transport system for L-ascorbate. These experiments are the first to show that ascorbate transport by osteoblastic cells responds to vitamin C deprivation and supplementation. Adaptation of transport activity to substrate availability may play an important role in the physiological regulation of intracellular ascorbate levels.

Adaptive regulation of ascorbate transport in osteoblastic cells.

Astrocytes possess a concentrativel-ascorbate (vitamin C) uptake mechanism involving a Na+-dependentl-ascorbate transporter located in the plasma membrane. The present experiments examined the effects of deprivation and supplementation of extracellularl-ascorbate on the activity of this transport system. Initial rates ofl-ascorbate uptake were measured by incubating primary cultures of rat astrocytes withl-[14C]ascorbate for 1 min at 37°C. We observed that the apparent maximal rate of uptake (V
max) increased rapidly (<1 h) when cultured cells were deprived ofl-ascorbate. In contrast, there was no change in the apparent affinity of the transport system forl-[14C]ascorbate. The increase inV
max was reversed by addition ofl-ascorbate, but notD-isoascorbate, to the medium. The effects of external ascorbate on ascorbate transport activity were specific in that preincubation of cultures withl-ascorbate did not affect uptake of 2-deoxy-D-[3H(G)]glucose. We conclude that the astroglial ascorbate transport system is modulated by changes in substrate availability. Regulation of transport activity may play a role in intracellular ascorbate homeostasis by compensating for regional differences and temporal fluctuations in external ascorbate levels.

/pdf/substrate-regulation-of-ascorbate-transport-activity-in-5g6vxj1b6h.pdf

Substrate regulation of ascorbate transport activity in astrocytes

Levels of ascorbic acid (AA) in the plasma, brain, and adrenal gland of rats were determined after 15 min of hypoxia (PaO2 less than 25 mm Hg) and following asphyxia. In rabbits, AA plasma levels were followed up to 75 min of reoxygenation following 15 min of hypoxia of the same severity. A significant increase (approximately 70%) in AA levels was found in plasma of rats and rabbits after hypoxia and asphyxia. This increase was found to be transient, with a return to normal levels within 1 h after resumption of normal oxygenation. Pretreatment with dexamethasone reduced the increase in AA level in both rabbits and rats. Adrenalectomy in rats, performed 24 h before the experiment, abolished the response to hypoxia. Ascorbate levels in the cerebral cortex, hypothalamus, and adrenal gland of awake rats subjected to hypoxia or asphyxia were found to be the same as in normoxic rats. Our results suggest that the observed changes in plasma AA levels are probably mediated through adrenocorticotropic hormone and that the adrenal gland is the major source of ascorbate efflux into the circulation during oxygen deprivation.

Effect of acute hypoxia on ascorbate content of plasma, cerebral cortex, and adrenal gland.

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Effect of acute hypoxia on ascorbate content of plasma, cerebral cortex, and adrenal gland.