Anticonvulsant action and biochemical effects in DBA/2 mice of CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate), a novel N-methyl-D-aspartate antagonist.
CPP has a potent anticonvulsant effect against sound-induced seizures in audiogenic DBA/2 mice. Pretreatment with CPP (0.01-10 nmol i.c.v., 45 min) protects against successive phases of sound-induced seizures in a dose-dependent fashion (ED50, tonic phase, 0.023 nmol; clonic phase, 0.039 nmol; wild running, 0.17 nmol). Systemic administration of CPP (0.001-0.1 mmol/kg i.p., 45 min) produces a similar protection (ED50, tonic phase, 0.0012 mmol/kg; clonic phase, 0.0026 mmol/kg; wild running, 0.021 mmol/kg). Following the administration of a fully anticonvulsant dose of CPP (0.1 mmol/kg i.p., 45 min) to adult DBA/2 mice regional brain glucose (cerebellum and striatum) levels are elevated and lactate (striatum and hippocampus) levels decrease. The CPP-induced changes in alanine, serine and glycine paralleled those of lactate. Aspartate levels are significantly decreased by CPP in the striatum (-21%) and the hippocampus (-23%).
Chapman
A G
AG
Department of Neurology, Institute of Psychiatry, De Crespigny Park, London.
Meldrum
B S
BS
Nanji
N
N
Watkins
J C
JC
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001923:Brain Chemistry / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016202:N-Methylaspartate; D010879:Piperazines / Q000494:pharmacology*
D000596:Amino Acids; D000927:Anticonvulsants; D007773:Lactates; D010879:Piperazines; D001224:Aspartic Acid; D019344:Lactic Acid; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D005947:Glucose