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Inhibitory effects of alcohol on glucose transport across the blood–brain barrier leads to neurodegeneration: preventive role of acetyl-l-carnitine

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Abstract

Purpose

Evidence shows that alcohol intake causes oxidative neuronal injury and neurocognitive deficits that are distinct from the classical Wernicke-Korsakoff neuropathy. Our previous findings indicated that alcohol-elicited blood-brain barrier (BBB) damage leads to neuroinflammation and neuronal loss. The dynamic function of the BBB requires a constant supply and utilization of glucose. Here we examined whether interference of glucose uptake and transport at the endothelium by alcohol leads to BBB dysfunction and neuronal degeneration.

Material and methods

We tested the hypothesis in cell culture of human brain endothelial cells, neurons and alcohol intake in animal by immunofluorescence, Western blotting and glucose uptake assay methods.

Results

We found that decrease in glucose uptake correlates the reduction of glucose transporter protein 1 (GLUT1) in cell culture after 50 mM ethanol exposure. Decrease in GLUT1 protein levels was regulated at the translation process. In animal, chronic alcohol intake suppresses the transport of glucose into the frontal and occipital regions of the brain. This finding is validated by a marked decrease in GLUT1 protein expression in brain microvessel (the BBB). In parallel, alcohol intake impairs the BBB tight junction proteins occludin, zonula occludens-1, and claudin-5 in the brain microvessel. Permeability of sodium fluorescein and Evans Blue confirms the leakiness of the BBB. Further, depletion of trans-endothelial electrical resistance of the cell monolayer supports the disruption of BBB integrity. Administration of acetyl-l-carnitine (a neuroprotective agent) significantly prevents the adverse effects of alcohol on glucose uptake, BBB damage and neuronal degeneration.

Conclusion

These findings suggest that alcohol-elicited inhibition of glucose transport at the blood-brain interface leads to BBB malfunction and neurological complications.

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Abbreviations

ALC:

Acetyl-l-carnitine

act-D:

Actinomycin D

BBB:

Blood–brain barrier

CB:

Cytochalasin B

ChAT:

Choline acetyltransferase

Chx:

Cycloheximide

DMSO:

Dimethyl sulfoxide

EB:

Evans Blue

EtOH:

Ethanol

GFAP:

Glial fibrillar acidic protein

GLUT:

Glucose transporter protein

hBECs:

Human brain endothelial cells

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide

NaFl:

Sodium fluorescein

NF:

Neurofilament

TEER:

Trans-endothelial electrical resistance

TH:

Tyrosine hydroxylase

vWF:

von Willebrand factor

ZO-1:

Zonula occludens-1

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Acknowledgments

This work was supported in part by NIH/NIAAA grant AA016403-01A2 (to JH) and by University of Nebraska Medical Center Faculty Retention Fund. Primary human endothelial cells were kindly provided by Dr. Yuri Persidsky.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Neurovascular Oxidative Injury, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    P. M. Abdul Muneer, Saleena Alikunju, Adam M. Szlachetka & James Haorah

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  1. P. M. Abdul Muneer
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  2. Saleena Alikunju
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  3. Adam M. Szlachetka
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  4. James Haorah
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Correspondence to James Haorah.

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Muneer, P.M.A., Alikunju, S., Szlachetka, A.M. et al. Inhibitory effects of alcohol on glucose transport across the blood–brain barrier leads to neurodegeneration: preventive role of acetyl-l-carnitine. Psychopharmacology 214, 707–718 (2011). https://doi.org/10.1007/s00213-010-2076-4

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  • DOI: https://doi.org/10.1007/s00213-010-2076-4

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