Quinolinic acid-induced seizures, but not nerve cell death, are associated with extracellular Ca2+ decrease assessed in the hippocampus by brain dialysis.
Seizures, neuronal damage and extracellular Ca2+ concentration were studied in rats unilaterally injected in the dorsal hippocampus with quinolinic acid, a brain metabolite with excitotoxic properties. In freely moving animals, in the first 2 h after the injection of a convulsant and neurotoxic dose (156 nmol), quinolinic acid induced a tetrodotoxin-insensitive decrease in the extracellular Ca2+ concentration (nadir 40%) in the injected area, as assessed by brain dialysis coupled to a fluorimetric method for Ca2+ detection. Blockade of quinolinic acid-induced decrements in Ca2+ by 15.6 nmol D-(-)2-amino-7-phosphonoheptanoic acid indicated that this effect was receptor-mediated. Dose-response relationships showed a close association between seizure activity (measured by EEG) and extracellular Ca2+ changes in the injected area. Changes in Ca2+ were apparent at the site of injection prior to the onset of focal seizures and they were not found in the homotypic structure where seizures were conducted. Drugs effective in blocking seizures (carbamazepine and flunarizine) prevented the fall in extracellular Ca2+, while drugs without anticonvulsant activity (ethosuximide and nifedipine) did not. Destruction of nerve cells by quinolinic acid was not prevented by treatment with carbamazepine and flunarizine. The results suggest that the fall in extracellular Ca2+ observed in the first 2 h after quinolinic acid, probably reflecting the ion influx into neurons, is involved in triggering focal seizures but is not related to the occurrence of nerve cell death.
Vezzani
A
A
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Wu
H Q
HQ
Angelico
P
P
Stasi
M A
MA
Samanin
R
R
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003956:Dialysis; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D000596:Amino Acids; D011725:Pyridines; D011805:Quinolinic Acids; D013779:Tetrodotoxin; D014701:Veratridine; D015763:2-Amino-5-phosphonovalerate; D017378:Quinolinic Acid; C031231:2-amino-7-phosphonoheptanoic acid; D002118:Calcium