Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate.
Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up-regulated pharmacologically. Here we show that chronic treatment of rats with the anti-epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose-dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [(3)H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose-dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate-activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.
Hassel
B
B
Norwegian Defence Research Establishment, Kjeller, Norway Neurological Department, National Hospital, Oslo, Norway. bjornar.hassel@ffi.no
Iversen
E G
EG
Gjerstad
L
L
Taubøll
E
E
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D027322:Amino Acid Transport System X-AG; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001693:Biological Transport, Active; D004591:Electrophoresis, Polyacrylamide Gel; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000096:biosynthesis / Q000235:genetics; D016704:Synapsins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000596:Amino Acids; D000927:Anticonvulsants; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D017981:Receptors, Neurotransmitter; D016704:Synapsins; D018698:Glutamic Acid; D014635:Valproic Acid; D005972:Glutaminase