Contrasting effects of D- and L-(E)-4-(3-phosphono-2-propenyl)piperazine-2-carboxylic acid as anticonvulsants and as inhibitors of potassium-evoked increases in hippocampal extracellular glutamate and aspartate levels in freely moving rats.
Microdialysis experiments performed in the dorsal hippocampus of freely moving rats showed that L-(E)-4-(3-phosphono-2-propenyl)piperazine-2-carboxylic acid (L-CPPene) is 10 times as potent as D-CPPene in inhibiting potassium-induced increases in extracellular levels of aspartate and glutamate. In control experiments, two 100 mM KCl stimuli (S1 and S2) applied for 10 min each (separated by a 40-min recovery period) produced substantial (300-500%) increases in the extracellular levels of aspartate, glutamate, taurine, and GABA and a 50% decrease in the glutamine level. S2/S1 ratios in the control groups were 0.67 (aspartate), 0.78 (glutamate), 0.83 (GABA), and 0.85 (taurine). In the experimental groups, D- or L-CPPene was applied via the probe during the second potassium stimulus (S2). L-CPPene (25 or 250 microM) produced selective suppression of potassium-induced increases of extracellular glutamate (S2/S1 ratio: 0.25) and aspartate (S2/S1 ratio: 0.20) levels, whereas 250 microM D-CPPene was required to inhibit the extracellular aspartate and glutamate increases. Neither enantiomer of CPPene affected the potassium-induced increases of GABA and taurine or the decrease in extracellular glutamine concentration. An additional study comparing the anticonvulsant potencies of D- and L-CPPene was performed using audiogenic DBA/2 mice. The anticonvulsant potency of D-CPPene, as assessed against sound-induced seizures in DBA/2 mice, was an order of magnitude higher than that of L-CPPene [ED50 clonic phase (intraperitoneal, 45 min): 1.64 mumol/kg and 16.8 mumol/kg, respectively]. We attribute the anticonvulsant action of D-CPPene to its antagonist action at the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Millan
M H
MH
Department of Neurology, Institute of Psychiatry, London, England.
Chapman
A G
AG
Meldrum
B S
BS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001224:Aspartic Acid / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D010879:Piperazines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013654:Taurine / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D005971:Glutamates; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride