The pyrimidine-derivative, BW1003C87, protects CA1 and striatal neurons following transient severe forebrain ischaemia in rats. A microdialysis and histological study.
The four vessel occlusion model of severe transient global ischaemia in Wistar rats has been used to study changes in the extracellular concentration of amino acids in hippocampus and striatum during and after ischaemia. We have investigated the effect of a pyrimidine derivative. BW1003C87 [5-(2,3,5-trichlorophenyl) pyrimidine-2,4-diamine 1.1 ethanesulphonate], 10 or 20 mg/kg, administered before or after ischaemia, on the amino acid accumulation and the pathological outcome. BW1003C87, 10 or 20 mg/kg, given intraperitoneally 20 min prior to ischaemia significantly reduces the extracellular accumulation of the amino acid in hippocampus and in striatum. BW1003C87, 10 or 20 mg/kg, injected 20 min prior to and 4 h after ischaemia protects against the hippocampal (CA1) and the striatal lesions. Administration of BW1003C87, 20 mg/kg, at 0 and 4 h or at 2 and 6 h post-ischaemia, significantly reduces CA1 lesions whereas no significant protection is seen in the striatum. These data indicate that BW1003C87 is able to inhibit the extracellular accumulation of amino acids during severe forebrain ischaemia. The compound is also a potent neuroprotector in this model (in which N-methyl-D-aspartate receptor antagonists fail to protect CA1 neurons). The effect of BW1003C87 on ischaemic glutamate release may contribute to protection in the striatum; it cannot explain the neuroprotection in CA1 since delayed administration is still highly protective. An action on voltage-sensitive sodium channels may contribute to the effects on amino acid release and to the cerebroprotective effect.
Lekieffre
D
D
Department of Neurology, Institute of Psychiatry, London, U.K.
Meldrum
B S
BS
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016548:Prosencephalon; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D005971:Glutamates; D011743:Pyrimidines; C078265:5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid