Brain glucose metabolism reaches metabolic extremes between human seizures. This study will determine if blood-brain barrier (BBB) capillary glucose transporter activity undergoes up-and down-regulation in response to seizures, and coincidentally seek a possible role of this Glut 1 transporter contributing to the interictal hypometabolism seen in PET studies. Recent work from our laboratory indicates that in pathological conditions, two distinctly different configurations of transporter protein density are seen. Large endothelia, with abundant Glut 1 transporter protein in the membranes; or smaller endothelia, with markedly less membrane Glut 1 transporter. This pattern suggests the possibility that discrete brain regions (on the order of a few cubic microns) may have markedly different glucose concentrations. It is postulated this paradigm may be an anticonvulsant adaptation, whereby epileptogenic neurons are inhibited by controlled access to substrate. We propose that in interictal epilepsy, BBB Glut 1 levels are down- regulated. Dynamic FDG-PET analyses of focal epilepsy patients with a previously identified hypometabolic zone should show reduced influx. In resected brain, quantitative immunogold studies of human capillary Glut 1 should show altered glucose transporter densities. In animal models of epilepsy, down-regulation of the BBB Glut 1 glucose transporter can presumably be more fully confirmed with """"""""(interictal) quantitative Western blot studies of microvessels, together with in vivo analyses of transporter maximal velocity, and electron microscopic quantification of Glut 1 transporters. In acute seizures, the opposite situation is anticipated. Presumably, ictal upregulation of the BBB Glut 1 transporter can be demonstrated with seizure onset (in animal models, using similar methods), and subcellular mechanisms which control capillary Glut 1 levels can be analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037360-03
Application #
6330535
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-02-10
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$177,485
Indirect Cost
Name
Brentwood Biomedical Research Institute
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
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Cornford, Eain M; Hyman, Shigeyo; Cornford, Marcia E (2003) Immunogold detection of microvascular proteins in the compromised blood-brain barrier. Methods Mol Med 89:161-75
Cornford, Eain M; Cornford, Marcia E (2002) New systems for delivery of drugs to the brain in neurological disease. Lancet Neurol 1:306-15
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Cornford, E M; Nguyen, E V; Landaw, E M (2000) Acute upregulation of blood-brain barrier glucose transporter activity in seizures. Am J Physiol Heart Circ Physiol 279:H1346-54
Kogai, T; Curcio, F; Hyman, S et al. (2000) Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression. J Endocrinol 167:125-35
Cornford, E M (1999) Epilepsy and the blood brain barrier: endothelial cell responses to seizures. Adv Neurol 79:845-62