Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction
© Muneer et al; licensee BioMed Central Ltd. 2011
Received: 14 August 2010
Accepted: 22 March 2011
Published: 22 March 2011
Methamphetamine (METH), an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB) function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB) to date.
In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM) increased the expression of glucose transporter protein-1 (GLUT1) in primary human brain endothelial cell (hBEC, main component of BBB) without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB) aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function.
Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.
Methamphetamine (METH), a highly addictive drug is a potent CNS stimulant that produces euphoric effects by promoting the release of dopamine, serotonin and norepinephrine . METH abuse and trafficking are increasing law enforcement and social health problems in the United States, particularly in the mid-western states where the rates of METH users among teenagers (12-17 years) and young adults (18-25 years) are highest in the country . The escalating problems due to METH abuse are enormous financial and health burdens to family and society. The ability of METH to stimulate the release of dopamine rapidly from dopaminergic neurons in the reward regions of the brain produces intense euphoric effects . However, acute bingeing and chronic self-administration paradigms of METH abuse cause severe neurotoxicity, monoamine deficits, hyperthermia, cardiac arrhythmia, depression, addiction, and psychiatric problems due to neuronal damage .
Multiple mechanisms of METH-induced neurotoxicity have been reported including hyperthermia, dopamine depletion, microglial activation, free radical formation, intrinsic cell apoptosis, and cytokine production [5, 6]. Acute doses of METH produce hyperthermia that significantly contributes to neurotoxicity as a result of dopamine and intracellular METH accumulation [7, 8], while chronic METH abuse causes hypothermia without an associated dopamine and serotonin depletion . Interestingly, accumulation of dopamine in chronic self-administration of METH triggers the activation of microglia and loss of neurons in human brain of METH abusers [9, 10]. In animals, METH-induced loss of dopaminergic neurons and decreases in dopamine levels occur in specific brain regions [1, 11]. Rakic et al. (1989) demonstrated the blood-brain barrier disruption after chronic amphetamine administration in guinea pig . Recent review articles describe the cellular and molecular mechanisms of METH-induced neurotoxicity as a consequence of oxidative stress, blood-brain barrier breakdown, microgliosis, and activation of the apoptotic pathway [13, 14]. Disruption of mitochondrial membrane potential transition and imbalanced oxidative phosphorylation appears to regulate the oxidative stress condition and the caspase-dependent apoptosis due to chronic METH abuse [13, 14]. METH abuse is also shown to exert neurotoxic effects by increasing the secretion of pro-inflammatory cytokines IL-6 and TNF-alpha in the brain [15, 16].
In humans it is reported that METH abusers have severe dilated cardiomyopathy . In an animal model, Treweek et al. (2007) indicated glycation of endogenous proteins and production of pro-inflammatory cytokines as possible unrecognized molecular mechanisms of cardiovascular disease in chronic METH abusers . In an in vitro study, METH accelerates the beating rate and intracellular Ca2+ oscillation pattern in rat cardiomyocytes in culture . However, the underlying mechanisms of METH-elicited cardiovascular dysfunction are not well understood. In conjunction with cardiovascular damage, METH abuse appears to impair blood-brain barrier (BBB) vascular function. This includes brain hyperthermia and BBB breakdown by METH treatment [20, 21]. Recently, Sharma et al. (2009) and Ramirez et al. (2009) demonstrated the oxidative damage related BBB disruption and neurotoxicity by drug of abuse [22, 23].
These myriad effects of METH on cardio-neurovascular function and on astrogliosis-related neurotoxicity clearly emphasize the importance of the blood and brain interface. The blood-brain barrier, principally composed of the brain endothelium tight junction proteins, is a dynamic interface. BBB function is maintained at the expense of huge bio-energy consumption. Thus, efficient uptake and metabolism of glucose by endothelial cells regulates the selective barrier and the transport system of the interface. Importantly, the transport of glucose from the BBB into the brain regulates the energy-dependent survival of glial and neuronal cells. Brain endothelial specific glucose transporter protein 1 (GLUT1) facilitates the transport of glucose from the circulation into the brain. Brain endothelial has the highly glycosylated 55 kDa GLUT1 and the less glycosylated 45 kDa GLUT1 isoforms [24, 25]. GLUT1 is localized 11% in the luminal, 45% in intracellular pool, and 44% in the abluminal side of the microvessel [26, 27].
Here, we hypothesize that impairment of GLUT1 by METH at the brain endothelium can deprive glucose uptake, transport and utilization as source of energy requirement for dynamic BBB function and subsequent survival of the brain endothelial cells. We also explore the protective effect of acetyl-L-carnitine (ALC, a regulator of mitochondrial function) for prevention of GLUT1 and BBB damage from METH exposure. The primary function of ALC is transporting the long-chain fatty acids into the mitochondria for oxidation to generate ATP and it also acts as a precursor for neurotransmission. Thus, ALC is neuroprotective and often refers to as an anti-oxidant because ALC maintains the functional integrity of mitochondria by enhancing β-oxidation fatty acids for energy production [28, 29].
Effects of METH on glucose uptake and GLUT1 expression
METH administration inhibits glucose uptake in animal model
To determine whether chronic administration of a moderately high dose of METH can exert a similar effect to that of high dose in cell culture, a daily dose of 15 mg/kg body weight was given to mice by i.p injection for 5-6 weeks. Then equimolar of [3H]-glucose (2 μCi) and unlabelled glucose was infused through the right common carotid artery as described in methods section. Our data showed that 5-6 week administration of METH almost completely inhibited glucose transport into the frontal and occipital cortex of the brain (Figure 3C). ALC protected the adverse effect of METH on glucose transport, which was also observed in the mice behavior. In that mice given the METH alone were inactive and lethargic by week 5, whereas METH+ALC administered mice were still active as the control mice.
METH-induced inhibition of glucose uptake impairs BBB integrity
Acute and chronic METH exposure impairs BBB function
We found that a high concentration of METH (200 μM) significantly decreased the rate of glucose uptake and glucose transporter protein-1 (GLUT1) expression. This was followed by impairment of BBB integrity as indicated by the increased permeability of the molecular tracers in an in vivo studies and a decrease in trans-endothelial electrical resistance in primary hBEC culture. Interestingly, a low level of METH (20 μM) insignificantly elevated both glucose uptake and GLUT1 protein expression in hBECs in acute but not in chronic condition. We demonstrated here for the first time that interference of glucose uptake and transport at the brain endothelium by chronic METH exposure lead to BBB dysfunction. METH doses of 200 μM in cell culture and 15 mg/kg body weight in animal study are considered moderately high concentrations and our low dose is close to the blood of recreational users of METH (20-40 mg/kg) [30, 31]. The high dose users, who normally administer 100-1000 mg/kg may be equivalent to 100-200 μM blood levels . Since 50-70% of METH is metabolized to amphetamine, 4-hydroxymeth-amphetamine and norephedrine [32, 33], the levels of METH detected in the circulation represent the 30-50% un-metabolized methamphetamine.
Daily chronic intraperitoneal injection of METH (15 mg/kg body weight) in mice for 5-6 weeks almost completely inhibited the glucose transport across the BBB, which validated our in vitro findings. The METH-induced decrease in glucose transport across the BBB correlated with the diminished levels of GLUT1 protein expression in brain microvessels (the primary tissue components of BBB). It was interesting to find the existence of two distinct isoforms of GLUT1 at the BBB interface (microvessels) with a molecular size of 55 kDa and in the brain tissue with a molecular size of 45 kDa. Expression of these GLUT1 isoforms proteins was reduced by METH administration. Similar to these findings, it has been reported that 55 kDa GLUT1 is localized specifically in endothelial cells, whereas the 45 kDa isoform is expressed in the perivascular end-feet of astrocytes [24, 25]. Functionally, the 55 kDa isoform is highly glycosylated, while the 45 kDa is the less glycosylated isoform . We hypothesize that due to the dynamic nature of the BBB, the GLUT1 at this interface is mostly in the active N-glycosylated form ready to transport glucose from the peripheral circulation into the brain. The packaging of glucose into the transporter protein for delivery into the brain is possible only when GLUT1 is enzymatically glycosylated by acetylglucosamine. We suggest that once the GLUT1 (55 kDa) is translocated onto the abluminal side of the BBB, it releases the glucose at the perivascular region to the end-feet of astrocytes and neurons. Here, GLUT1 becomes mostly in the non-glycosylated 45 kDa isoform. It is possible that the weak traces of 55 kDa GLUT1 that we detected in protein extract from brain tissue may be a contamination of internal arterial vessels. Thus glycosylation of GLUT1 is crucial for functional integration and structural preservation .
We showed that METH-elicited inhibition of glucose uptake and suppression of GLUT1 protein at the interface were accompanied by disruption of BBB integrity. It was evident that decrease in tight junction (TJ) proteins by METH exposure led to enhanced permeability of dye/fluorescein tracers across the BBB and a huge decrease in trans-endothelial electrical resistance of the BBB. The METH-induced increase in permeability and decrease in electrical resistance across the BBB has been attributed to the toxicity of METH by some investigators [23, 35–37]. Here we attributed to the impairment of glucose uptake and transport at the endothelium as one of the factors for BBB dysfunction. The rationale was that co-administration of CB exacerbated the effects of METH on TJ protein expression, BBB permeability and almost completely abrogated the BBB electrical resistance. In order to meet the constant energy demand of the dynamic BBB function, it is possible that there is synergistic interaction between GLUT1 and TJ proteins. As such, interference in endothelial glucose uptake and GLUT1 function by METH is likely to disrupt TJ protein integrity and BBB function. The question of whether such a defective BBB function will enhance passive diffusion of glucose into the brain interstitial fluid (ISF) may require further investigation. However, based on available information, BBB damage and defective in blood-brain barrier GLUT1 function seem to decrease glucose levels in the brain, similar to what we observed here. For example, in neurological diseases such as aging-related Alzheimer disease [38, 39] and De Vivo disease/syndrome [40, 41], where BBB disruption and GLUT1 defect were clearly observed, the levels of glucose in brain interstitial fluid were decreased from the normal values. That is because transport of glucose across the BBB into the brain interstitial fluid is exclusively an endothelium GLUT1-dependent and gradient-independent process [42, 43]. Interestingly, alteration GLUT1 at the BBB has been shown to affect the facilitated entry of glucose and efflux of glucose from the brain rather than passive influx of glucose into the brain [40, 43].
Glucose is the main source of energy in the brain. Therefore inhibition of glucose transport across the BBB endothelium by METH is expected to disrupt the homeostasis of glucose metabolism and energy demands of the brain cells, such as the dynamic BBB function. In part, this may explain as to why METH abusers exhibit impairment of glucose metabolism in various brain regions such as the frontal white matter , the striatum and thalamus , the limbic and paralimbic region , and in rat hippocampus . We propose that impairment of GLUT1 function by METH exposure affects the rate of glucose uptake and metabolism (glycolysis) in brain endothelium, resulting in disruption of BBB integrity and endothelial cell death. However, METH exposure did not seem to affect the Krebs cycle because pyruvate oxidation appears to be active and normal in endothelial cells exposed to 100 μM METH. This finding suggests that the primary enzyme pyruvate dehydrogenase, which converts pyruvate to acetyl-coenzyme A was not severely damage by METH exposure. Further, stabilization of glucose uptake and GLUT1 protein levels by ALC from METH exposure may provide evidence for involvement of ALC in glucose metabolism. It is possible that ALC stabilizes the glycosylation of GLUT1 protein at the brain endothelium by donating an acetyl group to glucosamine so as to keep the acetylglucosamine functional. In this way ALC may be able to maintain the structure and functional integration of GLUT1 glycosylation at the BBB and recycle the less glycosylated GLUT1 in the neurovascular compartment. The question of whether inability of BBB to deliver normal glucose levels into the brain during METH abuse has impact on neurodegeneration is not within scope of the present study. It will require further comprehensive investigations to uncover this important issue both in vitro and in vivo studies.
Our data indicate that METH mediated impairment of glucose uptake and transport at the brain endothelium disrupts the BBB function for efficient delivery of glucose into the brain. Thus, destruction of GLUT1 function at the endothelium may be a possible underlying mechanism for BBB damage.
We purchased the antibodies to GLUT1 from Abcam (Cambridge, MA), antibodies to occludin and ZO-1 from Zymed (Invitrogen, Carlsbad, CA), and antibody to α-actin from Millipore (Billerica, MA). All secondary alexa fluor antibodies were purchased from Invitrogen. D-(2-3H)-glucose (5 mCi, 185 MBq) was purchased from PerkinElmer Life and Analytical Sciences (Waltham, MA). Cytochalasin B (CB), cycloheximide (Chx), actinomycin D (Acd) and acetyl-L-carnitine (ALC) were purchased from Sigma-Aldrich (St. Louis, MO).
Primary human brain endothelial cells (hBECs) were obtained from Dr. Persidsky's Lab, Temple University School of Medicine, and hBECs were cultured as described previously . Briefly, all cell culture plates and glass cover slips were pre-coated with type 1 rat-tail collagen (0.09 mg/mL in double distilled sterile water), aspirated the excess collagen and dried the plates overnight in sterile hood. For glucose uptake and viability assays, cells were cultured in 96-well plates (20,000 cells/well), for immunohistochemistry cells were plated on 12-well glass cover slips (40,000 cells/well) and for protein extractions cells were cultured in T75 cm2 flasks (1 × 106 cells/flask). DMEM/F-12 media containing 10 mM Hepes, 13 mM sodium bicarbonate (pH 7), 10% fetal bovine serum, penicillin and streptomycin (100 μg/ml each, Invitrogen) were used for cell culture. Cell culture media was changed every 3 days until tight monolayers were formed in about 6-8 days.
In vitroglucose uptake
Following the modified method of Takakura , D-(2-3H)-glucose uptake was performed on hBECs cultured in 96 well plates. Cells were exposed to 20 μM and 200 μM METH for 24 hr in the presence or absence of 10 μM cytochalasin B (CB, 10 mM stock was dissolved in DMSO) or 200 μM ALC in a CO2 incubator. Cells were then incubated overnight in glucose-free DMEM/F-12 media containing equimolar of D-(2-3H)-glucose (1.0 μCi) and non-radiolabeled glucose. After washing off the excess 3H-glucose with phosphate saline buffer (PBS), cellular protein was precipitated with 10% TCA at 4°C for 15 min. Following the manufacturer's instruction, precipitated proteins were transferred onto a 96 well nitrocellulose filter using the Unifilter-96 well Harvester (PerkinElmer, Waltham, MA). Using the Beckman 96 well plate reader, radioactivity was measured by β-top counter. METH concentrations of 20 and 200 μM were derived from dose- and time-dependent toxicity assay (5, 10, 20, 50, 100, 200, 500 and 1000 μM of METH for 24-72 hrs), in which 20 μM had no cell toxicity effects while 200 μM of METH showed about 20% cell death after 48 hr exposure. ALC concentration of 200 μM was derived from dose-dependent study of 50-5000 μM on cell viability. Concentration of CB higher than 20 μM was toxic to hBECs (derived from 1 - 100 μM CB concentrations).
Cell viability assay
Cell viability on hBEC was determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The assay is based on the cleavage of yellow tetrazolium salt to purple formazan crystals by metabolically active cells. Briefly, cells were cultured in 96-well microtiter plates up to 90-100% confluent. Then the cells were treated for 48 hr in the presence or absence of METH or Pyruvate, or in combination of METH+pyruvate in glucose-free media in culture. Cells were then incubated at 37°C for 45 minutes after adding 100 μl MTT (5 mg/ml MTT in 10% FBS in 1× PBS). Then 100 μl DMSO was added just after aspirating the MTT solution and the plates were incubated at room temperature for 15 min. Absorbance of the purple formazan was detected by a microtiter plate reader at 490 nm wavelength.
For immunocytochemistry, the hBECs were cultured on glass cover slips in 12 well flasks until 80-100% confluent. Cells were then treated with 20 μM and 200 μM METH with and without CB (10 μM) or ALC (200 μM) for 24 hours. For immunohistochemistry, tissue sections (8 μm thickness) were derived from chronic METH, METH+ALC or pair-fed control mice. Cells and tissue sections were washed with PBS, fixed in acetone-methanol (1:1 v/v) fixative, blocked the cellular antigen with 3% bovine serum albumin at room temperature for 1 hr in the presence of 0.4% Triton X-100, and incubated with respective primary antibodies such as mouse anti-GLUT1 (1:250 dilution), rabbit anti-von Willebrand factor (vWF) (1:150 dilution), rabbit anti-occludin (1:250 dilution) and rabbit anti-ZO-1 (1:250 dilution) overnight at 4°C. After washing with PBS, cells/tissue sections were incubated for 1 hr with secondary antibody: anti-mouse-IgG Alexa Fluor 488 for GLUT1; anti-rabbit-IgG Alexa Fluor 594 for vWF; anti-rabbit-IgG Alexa Fluor 488 for occludin and ZO-1. Cover slips were then mounted onto glass slides with immunomount containing DAPI (Invitrogen), and fluorescence microphotographs were captured by fluorescent microscopy (Eclipse TE2000-U, Nikon microscope, Melville, NY) using NIS elements (Nikon, Melville, NY) software. GLUT1 expression was also analyzed in brain microvessels that were surgically dissected under microscope.
The hBECs cultured in T-75 cm2 flasks were lysed with CellLytic-M (Sigma) for 30 min at 4°C, centrifuged at 14000 g, and then total cell lysates protein concentrations were estimated by BCA (Thermo Scientific, Rockford, IL). We loaded 20 μg protein/lane and resolved the various molecular weight proteins by SDS-PAGE on gradient gels (Thermo Scientific) and then transferred the protein onto nitrocellulose membranes. After blocking, membranes were incubated for overnight with polyclonal antibody against mouse anti-GLUT1 protein (1:1000, Abcam, Cambridge, MA), rabbit anti-occludin antibody (1:250 dilution) and rabbit anti-ZO-1 antibody (1:250 dilution) at 4°C followed by 1 hr incubation with horse-radish peroxidase conjugated secondary antibodies. Immunoreactive bands were detected by West Pico chemiluminescence substrate (Thermo Scientific). Data were quantified as arbitrary densitometry intensity units using the Gelpro32 software package (Version 3.1, Media Cybernetics, Marlow, UK).
To determine the integrity of BBB function, changes in trans-endothelial electrical resistance (TEER) across the BBB were analyzed by a highly sensitive 1600R ECIS system (Applied Biophysics, Troy, NY). The ECIS system provides real-time monitoring of changes in TEER. In brief, hBECs at 20000 cells/well were plated on collagen type I coated 8W10E electrode arrays (Applied Biophysics). Once tight cell monolayers were formed, stable TEER value was monitored for 1 hr prior to treatment of cell monolayers with 20 μM and 200 μM METH in the presence or absence of CB or ALC followed by 10 hr recording of TEER at 400 hz with 10 min intervals. Confluent cell monolayers demonstrated baseline TEER readings of 1100 to 1200 Ω.cm2.
In vivoglucose transport assay
Five-week old male C56/BL-6J mice purchased from Jackson Laboratory (Bar Harbor, ME) were maintained in sterile cages under pathogen-free conditions in accordance with institutional ethical guidelines for care of laboratory animals, National Institutes of Health (NIH) guidelines, and the Institutional Animal Care Use Committee. On the basis of weight matched, initially mice were grouped into control, METH and METH+ALC and they were fed the normal Lieber-DeCarli liquid-diet (Dyets, Inc. Bethlehem, PA) for 5-6 weeks. ALC was mixed in the liquid diet (1.0 mg/mL) and METH (15 mg/kg body weight) was administered daily by i.p injection for 5-6 weeks. After week 5 pair feeding of liquid-diet and monitoring the body weights, the control, METH and METH+ALC mice were anesthetized with ketamine (100 mg/kg body weight) and xylazine (10 mg/kg body weight), and equimolar of 2-3H-glucose (2 μCi) and unlabelled glucose in 100 μl of saline were infused through the right common carotid artery. After 1 hr, mice were euthanized and then microvessels were removed and tissues were dissected from different brain regions. Known tissue weights were homogenized with 100 μl of Krebs-Ringer phosphate-HEPES (KRPH) buffer, centrifuged at 12,000 rpm for 15 min, and 20 μl of supernatants from each condition was mixed with 4 mL of scintillation fluid. The levels of 2-3H-glucose in the samples were detected by liquid scintillation counter (Beckman) along with a standard curve of 2-3H-glucose that was run in parallel. Results were extrapolated from the standard curve and data were expressed as counts per minutes (cpm) per milligram tissue weight.
In vivoBBB permeability assay
Using the sodium fluorescein (NaFl) and Evans Blue (EB) tracer dye mixtures (5 μM each), the effect of METH on BBB permeability was examined in acute and chronic animal model following an established method . In acute studies, mice were anesthetized, infused with 100 μl of 200 μM of ALC or 20 μM of CB or 200 μM of METH via the common carotid artery. ALC was infused 30 min prior to METH infusion. After 1 hr of CB and METH infusion, NaFI/EB mixture was infused into the CCA and waited for another 30 min before euthanizing the animals. In chronic studies, the controls, METH (15 mg/kg body weight) and METH+ALC (ALC, 1.0 mg/mL) were given for 5-6 weeks as in glucose uptake assay. Daily i.p infusion of CB (20 μM) or CB+METH lasted for 7 days only because mice that received the CB+METH injection were getting weak by then. Mixture of NaFl/EB dyes was then infused directly into the right carotid artery as in acute studies. After decapitating, brains were removed, dissected, weighed and homogenized in 600 μl 7.5% (w/v) trichloroacetic acid (TCA). Resulting suspensions were divided into two aliquots (300 μl each). One aliquot was neutralized with 50 μl 5 N NaOH and measured by fluorimetry on a GENios microplate reader (excitation 485 nm, emission 535 nm) for NaFI determination. The other aliquot was centrifuged 10 min at 10000 rpm, 4°C, and the supernatant was measured by absorbance spectroscopy at 620 nm for EB determination. Standard curve was constructed by serial dilutions of a standard EB/NaFl solution in 7.5% TCA.
Values are expressed as the mean ± SEM. Within an individual experiment, each data point was determined from three to five replicates. Statistical analysis of the data used GraphPad Prism V5 (Sorrento Valley, CA). Comparisons between samples were performed by one-way ANOVA with Dunnett's post-hoc test. Differences were considered significant at P values ≤ 0.05.
Laboratory of Neurovascular Oxidative Injury, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198.
blood brain barrier
human brain endothelial cells
glucose transporter protein
trans endothelial electrical resistance
- and ZO-1:
This work was supported by UNMC Faculty Retention Fund. Primary human endothelial cells were kindly provided by Dr. Yuri Persidsky.
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