beta-alanine uptake is upregulated in FeCl3-induced cortical scars.
Glial uptake of beta-[14C]alanine (beta-Ala) was studied in male Sprague-Dawley rats after sub-pial iontophoresis of FeCl3 into the right motor strip. Models bearing a 15-day-old scar were selected because of the presence of strongly reactive glia induced by FeCl3. Behavioral seizures were observed by daily visual inspection in one third of the animals. The effects of intraperitoneal (i.p.) injections of DL-alpha-aminoadipic acid (DLaAA), which exerts specific gliotoxicity through glutamine synthetase (GS) inhibition, and of 3-mercaptoproprionic acid (3MP), a potent inhibitor of glutamic acid decarboxylase (GAD: the rate-limiting enzyme in the biosynthesis of gamma-aminobutyric acid [GABA]), were also examined. There was significant enhancement of beta-Ala uptake in the margins of the scars. Further increases of uptake were triggered by 3MP, and there was extensive recruitment of astrocytes within isocortex even at a distance from the edges of the scar. DL-alpha-Aminoadipic acid caused a slight decrease of beta-Ala uptake, which was selectively localized to the scar margins. Seizure activity was unchanged by high i.p. doses of DL alpha AA. Our results strongly suggest that beta-Ala has high affinity for normal and reactive astrocytes, and that the uptake can be significantly enhanced by lowering endogenous GABA levels in abnormal cortical tissues in and around FeCl3-lesions by inhibition of GAD. Enhancement of glial beta-Ala uptake appeared to depend heavily on increased endothelial transport of small neutral amino acids, in a process modulated by perivascular glia. This model of free radical neurotoxicity may help gain more insight into abnormal neuronal-glial interactions caused by lipid peroxidation.
Robitaille
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Y
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Kemball
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Sherwin
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D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001345:Autoradiography; D002540:Cerebral Cortex / Q000166:cytology / Q000293:injuries / Q000378:metabolism*; D002712:Chlorides; D004569:Electroencephalography; D005070:Evans Blue; D005290:Ferric Compounds / Q000008:administration & dosage / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007478:Iontophoresis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects; D015091:beta-Alanine / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002712:Chlorides; D005290:Ferric Compounds; D005904:Glial Fibrillary Acidic Protein; D015091:beta-Alanine; D005070:Evans Blue; D005680:gamma-Aminobutyric Acid; C024555:ferric chloride