Strategies for studies of neurotoxic mechanisms involving deficient transport of L-glutamate: antisense knockout in rat brain in vivo and changes in the neurotransmitter metabolism following inhibition of glutamate transport in guinea pig brain slices.
This communication briefly reviews characteristics of glutamate transport in the central nervous system and is involved in the aetiology of slow neurodegenerative diseases. Data in the literature suggest that antisense oligonucleotides targeted against glutamate transporters and administered in vivo over a period of days could be used to test the hypothesis. Data from our laboratory have indicated that single intraventricular doses of antisense oligonucleotides can also results in significant reductions in the numbers of substrate binding sites associated with glutamate transporters and may even cause subtle changes in their characteristics. In order to study metabolism in brain tissue, we have used 13C-nuclear magnetic resonance spectroscopy to analyse extracts of slices of guinea pig cerebral cortex exposed to glutamate transport inhibitor L-anti,endo-methanopyrrolidine dicarboxylate (L-a,e-MPDC). The results have shown-for the first time in an experimental model that preserves the relationship between glia and neurones within the context of brain tissue-that inhibition of L-glutamate transport can exert a significant influence on neurotransmitter-related metabolism. These findings suggest that metabolic disturbances caused by deficient glutamate transport could play a significant role in the death of neurones under pathological conditions in vivo.
Rae
C
C
Department of 1 Biochemistry, The University of Sydney, NSW, Sydney, Australia.
Lawrance
M L
ML
Dias
L S
LS
Provis
T
T
Bubb
W A
WA
Balcar
V J
VJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides
C090670:3,4-methanopyrrolidine dicarboxylate; D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D003998:Dicarboxylic Acids; D018377:Neurotransmitter Agents; D014179:Neurotransmitter Uptake Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D011759:Pyrrolidines; D013873:Thionucleotides; D001224:Aspartic Acid; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid