Thiamine Deficiency Results in Downregulation of the GLAST Glutamate Transporter in Cultured Astrocytes

Hazell, A. S., Pannunzio, P., Rama Rao, K. V., Pow, D. V. and Andrea Rambaldi (2003) Thiamine Deficiency Results in Downregulation of the GLAST Glutamate Transporter in Cultured Astrocytes. Glia, 43 2: 175-184. doi:10.1002/glia.10241


Author Hazell, A. S.
Pannunzio, P.
Rama Rao, K. V.
Pow, D. V.
Andrea Rambaldi
Title Thiamine Deficiency Results in Downregulation of the GLAST Glutamate Transporter in Cultured Astrocytes
Journal name Glia   Check publisher's open access policy
ISSN 0894-1491
Publication date 2003-01-01
Sub-type Article (original research)
DOI 10.1002/glia.10241
Volume 43
Issue 2
Start page 175
End page 184
Total pages 10
Editor B. Ransom
H. Kettemann
Place of publication New York
Publisher Wiley-Liss
Collection year 2003
Language eng
Subject C1
270000 Biological Sciences
780106 Political science and public policy
Abstract Pyrithiamine-induced thiamine deficiency (TD) is a well-established model of Wernicke's encephalopathy in which a glutamate-mediated excitotoxic mechanism may play an important role in determining selective vulnerability. In order to examine this possibility, cultured astrocytes were exposed to TD and effects on glutamate transport and metabolic function were studied. TD led to decreases in cellular levels of thiamine and thiamine diphosphate (TDP) after 24 h of treatment and decreased activities of the TDP-dependent enzymes alpha-ketoglutarate dehydrogenase and transketolase after 4 and 7 days, respectively. TD treatment for 10 days led to a reversible decrease in the uptake of [H-3]-D-aspartate, a nonmetabolizable analogue of glutamate. Kinetic analysis revealed that the uptake inhibition was caused by a 47% decrease in the V-max for uptake of [H-3]-D-aspartate, with no change in the K-m value. Immunoblotting showed that this decrease in uptake was due to an 81% downregulation of the astrocyte-specific GLAST glutamate transporter. Loss of uptake activity and GLAST protein were blocked by treatment with the protein kinase C inhibitor H7, while exposure to DCG IV, a group II metabotropic glutamate receptor (mGluR) agonist, resulted in improvement of [H-3]-D-aspartate uptake and a partial reversal of transporter downregulation. These results are consistent with our recent in vivo findings of a loss of astrocytic glutamate transporters in TD and provide evidence that TD conditions may increase phosphorylation. of GLAST, contributing to its downregulation. In addition, manipulation of group II mGluR activity may provide an important strategy in the treatment of this disorder. (C) 2003 Wiley-Liss, Inc.
Keyword Neurosciences
Cell Culture
Pyrithiamine
Glutamate Transporter
Excitotoxicity
Metabotropic Receptor
Alpha-ketoglutarate Dehydrogenase
Experimental Wernickes Encephalopathy
Induced Partial Necrosis
2 Experimental-models
Rat-brain
Adenosine-triphosphatase
Extracellular Glutamate
Neuroblastoma-cells
Dependent Enzymes
Oxidative Stress
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2004 Higher Education Research Data Collection
School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 32 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 34 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 12:07:22 EST