In vivo seizure induction and pharmacological preconditioning by domoic acid and isodomoic acids A, B and C.
To date, nothing is known of the pharmacological properties of isomers of domoic acid (DA) in vivo in mammals. Here we assessed the acute seizurogenic and toxic properties of DA, isodomoic acids A, B and C (Iso-A, -B, -C), and the therapeutic potential of these compounds as pharmacological preconditioning agents. DA, Iso-A, Iso-B, and Iso-C all produced significant dose-dependent increases in seizure activity following intrahippocampal administration; doses producing half maximal cumulative seizure scores (ED50) were 137 pmol, 171 pmol, 13,000 pmol, and 3150 pmol, respectively. Pharmacological preconditioning with low-dose DA or Iso-A, 60 min before a high test dose of DA produced a significant reduction in seizure scores. In contrast, Iso-B and Iso-C each failed to induce any detectable tolerance to high-dose DA. Radioligand binding indicated a significant correlation between seizurogenic potency and kainate receptor affinity with KIs of 2.4 nM, 4.4 nM, 4990 nM and 170 nM for DA, Iso-A, Iso-B and Iso-C, respectively. Our in vivo results indicate that DA and Iso-A are functionally equipotent in acute seizure induction by direct intrahippocampal administration, while Iso-B and Iso-C are distinctly less potent.
Sawant
P M
PM
Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, P.O. Box 913, Dunedin, New Zealand.
Holland
P T
PT
Mountfort
D O
DO
Kerr
D S
DS
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006538:Heptanoic Acids; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007536:Isomerism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D008297:Male; D008387:Marine Toxins / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control
D006538:Heptanoic Acids; D007608:Kainic Acid; D008387:Marine Toxins; D018092:Kainic Acid Receptors; C524833:isodomoic acid A; C504322:isodomoic acid C; C012301:domoic acid