Myo-inositol transport through the blood-brain barrier

The unidirectional transport of [³H]myo-inositol across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured using an in situ rat brain perfusion technique. Myo-inositol was transported across the blood-brain barrier by a low capacity, saturable system with a one-half saturation concentration of 0.1 mM. The permeability surface-area product was 6.2×10^–5S^–1 with a myo-inositol concentration of 0.02 mM in the perfusate. The myo-inositol stereoisomer scyllo-inositol but not (+)-chiro-inositol (both 1 mM) inhibited myo-inositol transfer through the blood-brain barrier. These observations provide evidence that myo-inositol is transferred through the blood-brain barrier by simple diffusion and a stereospecific, saturable transport system.     

Niacinamide transport through the blood-brain barrier

The unidirectional influx of niacinamide across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique employing [¹⁴C]niacinamide. Niacinamide was transported rapidly across the blood-brain barrier by a system that was not saturable with 10 mM niacinamide in the perfusate. However, with periods of perfusion longer than 30 seconds, there was substantial backflow of [¹⁴C]niacinamide into the perfusate. Niacinamide (1.7 M) transport through the blood-brain barrier was not significantly inhibited by 3-acetylpyridine. Thus, niacinamide is transported rapidly and bidirectionally through the blood-brain barrier by a high capacity transport system. Although involved in the transfer of niacinamide between blood and brain, this transport system does not play an important regulatory role in the synthesis of NMN, NAD, and NADP from niacinamide in brain.     

Pantothenic Acid Transport Through the Blood-Brain Barrier

The unidirectional influx of D-pantothenic acid (PA) across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique using [3H]D-PA (1.1 Ci/mmol). PA was transported across the blood-brain barrier by a saturable system that could be described by a Michaelis-Menten transport model with a half-saturation concentration and maximal influx rate of 19 microM and 0.21 nmol/g of brain/min, respectively. PA (0.3 microM) transport through the blood-brain barrier was significantly inhibited by probenecid, nonanoic acid, and biotin (all less than or equal to 0.25 mM), but not by penicillin G, pyruvate, beta-hydroxybutyrate, L-leucine (all 1 mM), or poly-L-lysine HBr (1 mg/ml). Probenecid (0.25 mM), nonanoic acid (0.5 mM), and PA (1.0 mM) did not inhibit [3H]L-leucine transport through the blood-brain barrier, whereas 30 microM-L-leucine inhibited [3H]leucine transport to 23% of control values. Thus, PA is transported through the blood-brain barrier by a low-capacity, saturable transport system with a half-saturation concentration approximately 10 times the plasma PA concentration. Although involved in the transfer of PA from blood into brain, this system does not play an important regulatory role in the synthesis of CoA from PA in brain.     

The Possible Role of Glutamate Uptake in Metaphit-Induced Seizures

In a study of the possible mechanism of action of metaphit and phencyclidine in the brain, the uptake of glutamate at the luminal side of the blood-brain barrier (BBB) was studied by means of an in situ brain perfusion technique in normal guinea pigs and in those pretreated with metaphit. Metaphit, an isothiocyanate analog of phencyclidine (PCP), induces time-dependent epileptogenic changes in the electroencephalogram in guinea pig, reaching a maximum 18–24 h after metaphit administration (50 mg/kg IP). In metaphit-pretreated animals a significant reduction of glutamate BBB uptake was found, in comparison with that of controls. Reduction of glutamate transport from blood to brain ranged from 77% to 79% in all brain structures studied. This inhibition was probably due to changes in the properties of saturable components responsible for transport of glutamate across the BBB. Kinetic measurements revealed a saturable amino acid influx into the parietal cortex, caudate nucleus, and hippocampus, with a Km between 3.1 and 5.1 M, and the V_max ranging from 14.3 to 27.8 pmol^–1 g^–1. The nonsaturable component, K_id, was statistically different from zero, ranging from 1.47 to 2.00 M min^–1 g^–1. Influx of glutamate into the brain was not altered in the presence of 1 mM D-aspartate, but it was significantly inhibited in the presence of 1 mM L-aspartate. We conclude that the cerebrovascular permeability of circulating glutamate is due to the presence of a higher-capacity saturable receptor and/or a carrier-mediated transport system (75%) and also a low-capacity diffusion transport system (25%) for the glutamate located at the luminal side of the BBB. The glutamate transport system is probably fully saturated at physiological plasma glutamate concentrations.     

Biotin Transport Through the Blood-Brain Barrier

The unidirectional influx of biotin across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique employing [3H]biotin. Biotin was transported across the blood-brain barrier by a saturable system with a one-half saturation concentration of approximately 100 microM. The permeability-surface area products were 10(-4) s-1 with a biotin concentration of 0.02 microM in the perfusate. Probenecid, pantothenic acid, and nonanoic acid but not biocytin or biotin methylester (all 250 microM) inhibited biotin transfer through the blood-brain barrier. The isolated rabbit choroid plexus was unable to concentrate [3H]biotin from medium containing 1 nM [3H]biotin. These observations provide evidence that: biotin is transported through the blood-brain barrier by a saturable transport system that depends on a free carboxylic acid group, and the choroid plexus is probably not involved in the transfer of biotin between blood and cerebrospinal fluid.     

Independent blood-brain barrier transport systems for nucleic acid precursors

The blood-brain barrier permeability to certain ¹⁴C-labelled purine and pyrimidine compounds was studied by simultaneous injection in conjunction with two reference isotopes into the rat common carotid artery and decapitation 15 s later. The amount of ¹⁴C-labelled base or nucleoside remaining in brain was expressed in relation to ³H₂O (a highly diffusible internal standard) and ^113mIn-labelled EDTA (an essentially non-diffusible internal standard).Of the 17 compounds tested, measurable, saturable uptakes were established for adenine, adenosine, guanosine, inosine and uridine.Two independent transport systems in the rat blood-brain barrier were defined. One transported adenine (K_m = 0.027 mM) and could be inhibited with hypoxanthine. Adenosine (K_m = 0.018 mM), guanosine, inosine and uridine all cross-inhibit, defining a second independent nucleoside carrier system. Adenosine inhibited [¹⁴C]uridine uptake more effectively than did uridine, suggesting a weaker affinity of uridine for this nucleoside carrier.     

Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol,and Moniliformin and Their Transfer to the Brain

Background

Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects.

Methods

Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and ¹⁴C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients.

Results

Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport.     

Independent blood-brain barrier transport systems for nucleic acid precursors.

The blood-brain barrier permeability to certain 14-C-labelled purine and pyrimidine compounds was studied by simultaneous injection in conjunction with two reference isotopes into the rat common carotid artery and decapitation 15s later. The amount of 14-C-labelled base or nucleoside remaining in brain was expressed in relation to 3-H2O (a highly diffusible internal standard) and 113m-In-labelled EDTA (an essentially non-diffusible internal standard). Of the 17 compounds tested, measurable, saturable uptakes were established for adenine, adenosine, guanosine, inosine and uridine. Two independent transport systems in the rat blood-brain barrier were defined. One transported adenine (Km equals 0.027 mM) and could be inhibited with hypoxanthine. Adenosine (Km equals 0.018 mM), guanosine, inosine and uridine all cross-inhibit, defining a second independent nucleoside carrier system. Adenosine inhibited [14-D]uridine uptake more effectively than did uridine, suggesting a weaker affinity of uridine for this nucleoside carrier.     

Blood-brain barrier transport of caffeine: Dose-related restriction of adenine transport

We studied the transport of ¹⁴C-caffeine across the blood-brain barrier (BBB) by measuring brain ¹⁴C:³H ratios five seconds after rats received the caffeine, with ³H₂O, by intracarotid injection. Caffeine was found to enter the brain by both simple diffusion and saturable, carrier-mediated transport. This latter observation suggested to us that caffeine's transport might involve macromolecules that are structurally similar to caffeine. Hence, we examined caffeine's ability to inhibit the BBB transports of ¹⁴C-adenosine and ¹⁴C-adenine. Caffeine caused a dose-dependent inhibition of ¹⁴C-adenine transport but no clear change in that of ¹⁴C-adenosine. At very high blood levels (K_i = 9.8 mM), caffeine may restrict the availability of circulating purines to the brain. This effect may be important neonatally, when carrier-mediated adenine transport apparently is maximal.     

Slow Penetration of Thyrotropin-Releasing Hormone Across the Blood-Brain Barrier of an In Situ Perfused Guinea Pig Brain

Transport of 3H-labelled thyrotropin-releasing hormone (TRH) across the blood-brain barrier was studied in the ipsilateral perfused in situ guinea pig forebrain. The unidirectional transfer constant (Kin) calculated from the multiple time brain uptake analysis ranged from 1.14 X 10(-3) to 1.22 X 10(-3) ml min-1 g-1, in the parietal cortex, caudate nucleus, and hippocampus. Regional Kin values for [3H]TRH were significantly reduced by 43-48% in the presence of an aminopeptidase and amidase inhibitor, 2 mM bacitracin, suggesting an enzymatic degradation of tripeptide during interaction with the blood-brain barrier. In the presence of unlabelled 1 mM TRH and 2 mM bacitracin together, a reduction of [3H]TRH regional Kin values similar to that obtained with 2 mM bacitracin alone was obtained . L-Prolinamide, the N-terminal residue of tripeptide, at a 10 mM level had no effect on the kinetics of entry of [3H]TRH into the brain. The data indicate an absence of a specific saturable transport mechanism for TRH presented to the luminal side of the blood-brain barrier. It is concluded that intact TRH molecule may slowly penetrate the blood-brain barrier, the rate of transfer being some three times higher than that of D-mannitol.     

Possible involvement of plasma histidine in differential brain permeability to zinc and cadmium

Zinc gets into the brain parenchyma across the blood-brain and the blood-cerebrospinal fluid barriers, while cadmium hardly gets into the brain parenchyma. Because histidine may be involved in zinc transport across the brain barrier systems, the binding to histidine was compared between zinc and cadmium to understand the difference in brain permeability to both metals. Sephadex G-10 gel filtration indicated that ¹⁰⁹Cd, unlike ⁶⁵Zn, does not bind to histidine. When the plasma incubated with ⁶⁵Zn or ¹⁰⁹Cd was dialyzed in physiological saline containing histidine (0-10 mM), ⁶⁵Zn concentration in the dialysate was increased with the increase of the histidine concentration, suggesting the transfer of zinc from plasma proteins to histidine. The low affinity of zinc to plasma proteins may be important for brain permeability to this metal. On the other hand, ¹⁰⁹Cd was not detected in the dialysate in the presence of 0.1 mM histidine, which is equal to the concentration in the plasma, suggesting no transfer of cadmium from plasma proteins to histidine. These results suggest that the avid binding of cadmium to plasma proteins is related to brain impermeability to this metal.     

Blood–Brain Transfer of Glucose and Glucose Analogs in Newborn Rats

Little is known of the selectivity of the blood-brain barrier at birth. Hexoses are transported through the barrier by a facilitating mechanism. To study the capacity of this mechanism to distinguish between analogs of D-glucose, we compared the transport of fluorodeoxyglucose, deoxyglucose, glucose, methylglucose, mannose, galactose, mannitol, and iodoantipyrine across the cerebral capillary endothelium in newborn Wistar rats. Cerebral blood flow, glucose consumption, and the blood-brain permeabilities of the hexoses were 25-50% of the adult values but the ratios between the permeabilities of the individual hexoses were similar to the ratios observed in adult rats. The mannitol clearance into brain was considerably higher than in adult rats (about 10-fold), indicating a higher endothelial permeability to small polar nonelectrolytes. The brain water content was higher in newborn than in adult rats and was associated with a higher steady-state distribution of labeled methylglucose between brain and blood. Hexose concentrations were determined relative to whole blood because the apparent erythrocyte membrane permeability to glucose was as high as in humans and thus considerably higher than in adult rats. The half-saturation concentration of glucose transport across the blood-brain barrier was considerably higher than in adult rats, about three-fold, suggesting that net blood-brain glucose transfer is less sensitive to blood glucose fluctuation in newborn than in adult rats.     

Cellular and whole-plant chloride dynamics in barley: insights into chloride–nitrogen interactions and salinity responses

The first analysis of chloride fluxes and compartmentation in a non-excised plant system is presented, examining ten ecologically pertinent conditions. The short-lived radiotracer couple ³⁸Cl/³⁹Cl was used as a Cl^– tracer in intact barley (Hordeum vulgare L. cv. Klondike) seedlings, which were cultured and investigated under four external [Cl^–], from abundant (0.1 mM) to potentially toxic (100 mM). Chloride–nitrogen interactions were investigated by varying N source (NO₃ ^– or NH₄ ⁺) and strength (0.1 or 10 mM), in order to examine, at the subcellular compartmentation level, the antagonism, previously documented at the influx level, between Cl^– and NO₃ ^–, and the potential role of Cl^– as a counterion for NH₄ ⁺ under conditions in which cytosolic [NH₄ ⁺] is excessive. Cytosolic [Cl^–] increased with external [Cl^–] from 6 mM to 360 mM. Cl^– influx, fluxes to vacuole and shoot, and, in particular, efflux to the external medium, also increased along this gradient. Efflux reached 90% of influx at the highest external [Cl^–]. Half-times of cytosolic Cl^– exchange decreased between high-affinity and low-affinity influx conditions. The relationship between cytosolic [Cl^–] and shoot flux indicated the presence of a saturable low-affinity transport system (SLATS) responsible for xylem loading of Cl^–. N source strongly influenced Cl^– flux to the vacuole, and moderately influenced Cl^– influx and shoot flux, whereas efflux and half-time were insensitive to N source. Cytosolic pool sizes were not strongly or consistently influenced by N source, indicating the low potential for Cl^– to act as a counterion to hyperaccumulating NH₄ ⁺. We discuss our results in relation to salinity responses in cereals.Abbreviations [Cl^–]_cyt cytosolic chloride concentration - [Cl^–]_o external chloride concentration     

Transport of 3-hydroxybutyrate by cultured rat brain astrocytes

It is well established that 3-hydroxybutyrate can serve as an energy source for the brain. Since substrate utilization may be regulated in part by transport across the cellular membrane, we investigated the uptake of 3-hydroxybutyrate by primary cultures of rat brain astrocytes. Measurement of the net uptake indicated a saturable system and a Lineweaver-Burke type plot was consistent with a single carrier-mediated mechanism with a Km of 6.03 mM and a Vmax of 32.7 nmol/30 seconds/mg protein. The rate of uptake at pH 6.2 was more than ten times the rate at pH 8.2, with the rate at pH 7.4 being intermediate between these values, suggesting the possibility of cotransport with H⁺ or exchange with OH^– (antiport). Mersalyl had only a slight effect on the transport of 3-hydroxybutyrate, suggesting that sulfhydryl groups are not involved in the transport of this monocarboxylic acid. Phenylpyruvate and -ketoisocaproate also attenuated the transport, but lactate had only a marginal effect. These results suggest that the utilization of 3-hydroxybutyrate as an energy source by astrocytes is regulated in part by carrier-mediated transport and that the uptake system is different from the lactate transport system.These data were presented in part at the FASEB Meeting, April, 1990     

Sodium influx in isolated gills of the freshwater mussel,Ligumia subrostrata

Summary Isolated gills of the freshwater mussel,Ligumia subrostrata, accumulate Na from a pondwater bathing medium. The rate of Na transport by the isolated gill is 13.2±1.1 mol (g dry gill·10 min)^–1 which equals or exceeds the estimated Na transport rate of intact animals. Sodium influx is saturable with aV _max of 13.6±1.2 mol (g dry gill·10 min)^–1 and an affinity (K _s) of 0.17 mM Na/l. The isolated gills survive prolonged exposure to pondwater with a constant of 890 l O₂ (g dry gill·h)^–1 over a 4 h period. Sodium transport in the isolated gills is stimulated 80% above control values by 10^–4 M serotonin, 60% by 0.5 mM cAMP and 60% by 12.5 g/ml nystatin. Sodium influx is inhibited by 0.5 mM amiloride and 1 mM lithium.     

Blood-brain glucose transfer in the mouse

The intracarotid injection method has been utilized to examine blood-brain barrier (BBB) glucose transport in normal mice, and after a 2-day fast. In anesthetized mice, cerebral blood flow (CBF) rates were reduced from 0.86 ml·min^–1·gm^–1 in control to 0.80 ml·min^–1·gm^–1 in fasted animals (p>0.05). Brain Uptake Indices were significantly (p<0.05) higher in fasted (plasma glucose =4.7 mM) than control (plasma glucose = 6.5 mM) mice, while plasma glucose was significantly lower. The maximal velocity (V_max) for glucose transport was 1562±303 nmoles·min^–1·g^–1, and the half-saturation constant (Km =) 6.67±1.46 mM in normally fed mice. In fasted mice the Vmax was 2053±393 nmoles·min^–1·g^–1 (p>0.05), and the half-saturation constant (Km =) 7.30±1.60 mM (not significant, P>0.05). A rabbit polyclonal antiserum to a synthetic peptide encoding the 13 C-terminal amino acids of the human erythrocyte glucose transporter (GLUT-1) immunocytochemically confirmed that the mouse brain capillary endothelial glucose transporter is a GLUT-1 transporter, and immunoreactivity was similar in brain endothelia from fed and fasted animals. In conclusion, after a 2-day fast in the mouse, we saw significant reductions in forebrain weight (7%), and plasma glucose levels (27%). Increased brain glucose extraction (25%, p<0.05), and a 22% increase in the unsaturatedpermeability-surface area product (p<0.05) was also observed.     

TRYPTOPHAN TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER DURING ACUTE HEPATIC FAILURE

Abstract— Tryptophan transport across the blood-brain barrier was studied using a single injection dual isotope label technique, in the following three conditions: normal rats, rats with portacaval shunts, and rats with portacaval shunts followed 65 h later by hepatic artery ligation. In both normal rats and those with acute hepatic failure the tryptophan transport system was found to be comprised of two kinetically distinct components. One component was saturable and obeyed Michaelis-Menten kinetics (normal: V_max= 19.5 nmol.min^?1.g^?1. K_m= 113 μM; hepatic failure: V_max, = 33.8 nmol.min^?1.g^?1, K_m= 108 μM), and the second was a high capacity system which transported tryptophan in direct proportion to concentration over the range tested (normal: K= 0.026 ml.min^?1.g^?1; hepatic failure: K= 0.067 ml.min^?1.g^?1). Since the saturable low capacity component transports several neutral amino acids, and their collective plasma concentration is high in relation to the individual K_ms, tryptophan transport by this component is reduced by competitive inhibition under physiological conditions. Thus it was calculated that in normal rats approx 40% of tryptophan influx occurs via the high capacity system. During acute hepatic failure transport via both components was increased substantially, approximately doubling the rate of tryptophan penetration of the blood-brain barrier at all concentrations tested. The contribution by the high capacity component became even more significant than in normal rats, accounting for about 75% of all tryptophan passage from plasma to brain. Brain tryptophan content was 29.9 nmol/g in normal rats and rose to 45.2 nmol/g in rats with portacaval shunts and 50.5 nmol/g in those with acute hepatic failure, correlating with the increased rate of tryptophan transport. In a previous study we found that plasma competing amino acids were greatly increased during acute hepatic failure. Calculations predict that these increased concentrations would cause a reduction in tryptophan transport by the low capacity system. However, because of the increase in the rate of transport by the high capacity component, net tryptophan entry across the blood-brain barrier was actually increased. This increased rate of transport clearly contributes to the increased content of brain tryptophan found during hepatic failure.     

Transferrin and Transferrin Receptor Function in Brain Barrier Systems

1. Iron (Fe) is an essential component of virtually all types of cells and organisms. In plasma and interstitial fluids, Fe is carried by transferrin. Iron-containing transferrin has a high affinity for the transferrin receptor, which is present on all cells with a requirement for Fe. The degree of expression of transferrin receptors on most types of cells is determined by the level of Fe supply and their rate of proliferation.2. The brain, like other organs, requires Fe for metabolic processes and suffers from disturbed function when a Fe deficiency or excess occurs. Hence, the transport of Fe across brain barrier systems must be regulated. The interaction between transferrin and transferrin receptor appears to serve this function in the blood–brain, blood–CSF, and cellular–plasmalemma barriers. Transferrin is present in blood plasma and brain extracellular fluids, and the transferrin receptor is present on brain capillary endothelial cells, choroid plexus epithelial cells, neurons, and probably also glial cells.3. The rate of Fe transport from plasma to brain is developmentally regulated, peaking in the first few weeks of postnatal life in the rat, after which it decreases rapidly to low values. Two mechanisms for Fe transport across the blood–brain barrier have been proposed. One is that the Fe–transferrin complex is transported intact across the capillary wall by receptor-mediated transcytosis. In the second, Fe transport is the result of receptor-mediated endocytosis of Fe–transferrin by capillary endothelial cells, followed by release of Fe from transferrin within the cell, recycling of transferrin to the blood, and transport of Fe into the brain. Current evidence indicates that although some transcytosis of transferrin does occur, the amount is quantitatively insufficient to account for the rate of Fe transport, and the majority of Fe transport probably occurs by the second of the above mechanisms.4. An additional route of Fe and transferrin transport from the blood to the brain is via the blood–CSF barrier and from the CSF into the brain. Iron-containing transferrin is transported through the blood–CSF barrier by a mechanism that appears to be regulated by developmental stage and iron status. The transfer of transferrin from blood to CSF is higher than that of albumin, which may be due to the presence of transferrin receptors on choroid plexus epithelial cells so that transferrin can be transported across the cells by a receptor-mediated process as well as by nonselective mechanisms.5. Transferrin receptors have been detected in neurons in vivo and in cultured glial cells. Transferrin is present in the brain interstitial fluid, and it is generally assumed that Fe which transverses the blood–brain barrier is rapidly bound by brain transferrin and can then be taken up by receptor-mediated endocytosis in brain cells. The uptake of transferrin-bound Fe by neurons and glial cells is probably regulated by the number of transferrin receptors present on cells, which changes during development and in conditions with an altered iron status.6. This review focuses on the information available on the functions of transferrin and transferrin receptor with respect to Fe transport across the blood–brain and blood–CSF barriers and the cell membranes of neurons and glial cells.     

Transport of quinolinic acid into rabbit and rat brain

The transport metabolism of [³H]quinolinic acid in the central nervous system of rabbits and rats were studied. In vitro [³H]quinolinic acid was not readily accumulated by isolated choroid plexus. After the intraventricular injection of tracer quantities of [³H]quinolinic acid, the [³H]quinolinic acid did not enter the brain as readily as concurrently injected [¹⁴C]mannitol and was not metabolized, The permeability-surface area constant for [³H]quinolinic acid at the rat blood-brain barrier was 1.5±1.3×10^–5 sec^–1 compared to 2.8±0.4×10^–5 sec^–1 for [³H]mannitol. Our results suggest that: 1) [³H]quinolinic acid is transported in the CNS by passive diffusion and 2) is not metabolized.     

Studies on blood-brain barrier permeability after microwave-radiation

Summary Since the reported alterations of permeability of the blood-brain barrier by microwave radiation have implications for safety considerations in man, studies were conducted to replicate some of the initial investigations. No transfer of parenterally-administered fluorescein across the blood-brain barrier of rats after 30 min of 1.2-GHz radiation at power densities from 2–75 mW/cm² was noted. Increased fluorescein uptake was seen only when the rats were made hyperthermic in a warm-air environment. Similarly, no increase of brain uptake of¹⁴C-mannitol using the Oldendorf dual isotope technique was seen as a result of exposure to pulsed 1.3-GHz radiation at peak power densities up to 20 mW/cm², or in the continuous wave mode from 0.1–50 mW/cm². An attempt to alter the permeability of the blood-brain barrier for serotonin with microwave radiation was unsuccessful. From these studies it would appear that the brain must be made hyperthermic for changes in permeability of the barrier induced by microwave radiation to occur.The research reported in this paper was conducted by personnel of the Radiation Sciences Division, USAF School of Aerospace Medicine, Brooks AFB, Tex. 78235. The animals involved in the study were procured, maintained, and used in accordance with the Animal Welfare Act of 1970 and the Guide for the Care und Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council