The food-associated fungal neurotoxin ochratoxin A inhibits the absorption of glutamate by astrocytes through a decrease in cell surface expression of the excitatory amino-acid transporters GLAST and GLT-1.
The food-associated mycotoxin ochratoxin A (OTA) has been demonstrated to be deleterious to numerous cell types including brain cells. Although OTA has been proved to be toxic to astrocytes, no other investigation has been conducted on the impact of OTA on astrocytic functions. In the present study, we evaluated the effect of OTA on one of the major astrocytic functions, i.e. the reabsorption of extracellular glutamate. We found that OTA suppressed glutamate absorption by rat cortical astrocytes with a half inhibitory concentration of 1.3 and 10.1 microM in the absence and presence of fetal calf serum. Although OTA inhibits glutamine synthetase activity, this effect was not involved in OTA-mediated alteration of glutamate absorption since decrease in enzyme activity only occurred at high cytotoxic concentrations of toxin (100 microM). Similarly, alterations in the expression of the excitatory amino-acid transporters were not involved since OTA failed to modify total expression level of GLAST and GLT-1. We found that inhibition of glutamate absorption by OTA was due to a decrease in the expression of GLAST and GLT-1 at the cell surface. We propose that, in addition to being directly toxic to neurons and astrocytes, OTA could also cause the death of brain cells through inhibition of glutamate uptake by astrocytes, leading to the accumulation of extracellular glutamate and ultimately to excitotoxicity.
Razafimanjato
Helisoa
H
Laboratoire des Interactions Moléculaires et Systèmes Membranaires, CRN2M, CNRS UMR 6231, INRA USC 2027, University of Aix-Marseille 2 and Aix-Marseille 3, Faculté des Sciences de St-Jérôme, 13397 Marseille Cedex 20, France.
Garmy
Nicolas
N
Guo
Xiao-Jun
XJ
Varini
Karine
K
Di Scala
Coralie
C
Di Pasquale
Eric
E
Taïeb
Nadira
N
Maresca
Marc
M
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D009793:Ochratoxins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D009498:Neurotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D018698:Glutamic Acid; D005974:Glutamate-Ammonia Ligase