Intrastriatal injection of DL-alpha-aminoadipate reduces kainate toxicity in vitro.
Intrastriatal injection of the excitatory amino acid analogue DL-alpha-aminoadipate (100 micrograms in 2 microliters saline, pH 7.4) into anesthetized rats caused a significant reduction in striatal glutamine synthetase activity in the ipsilateral compared to the contralateral striatum 6 h after the injection. Striatal neurons were unaffected by this treatment, and by 24 h after the injection, glutamine synthetase activity had returned to normal. In contrast to the situation in vivo, incubation of coronal slices (which included the striatum) in vitro with DL-alpha-aminoadipate (1-3 mM) for periods of up to 1 h caused no change in glutamine synthetase activity. Increased doses of DL-alpha-aminoadipate coupled with longer incubation times led to widespread neuronal degeneration within the striatum. Preparation of coronal slices from striata which had been injected 6 h previously with DL-alpha-aminoadipate, and subsequently incubated with 300 microM kainate, showed a marked survival of some neurons particularly those ordering the injection tract. The toxicity of 500 microM N-methyl-D-aspartate in similar slices was unchanged. Conversely, co-incubation of DL-alpha-aminoadipate with excitotoxins in vitro provided protection of striatal cells against degeneration by N-methyl-D-aspartate, but not kainate. These findings suggest that, in vivo, DL-alpha-aminoadipate has a specific effect on glial cell metabolism which, in contrast to incubation of coronal slices with the compound in vitro, is not related to the amino acid antagonist properties associated with the D-isomer. Thus, the reduced toxicity of kainate observed in striatal slices following DL-alpha-aminoadipate injection in vivo may indicate a non-neuronal site of action of kainate.
McBean
G J
GJ
Department of Biochemistry, Trinity College, Dublin 2, Ireland.
D015074:2-Aminoadipic Acid / Q000494:pharmacology*; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity*; D009457:Neuroglia / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D000600:Amino Acids, Dicarboxylic; D015074:2-Aminoadipic Acid; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid