Sequelae of parenteral domoic acid administration in rats: comparison of effects on different metabolic markers in brain.
Parenterally administered domoic acid, a structural analog of the excitatory amino acids glutamic acid and kainic acid, has specific effects on brain histology in rats, as measured using different anatomic markers. Domoic acid-induced convulsions affects limbic structures such as hippocampus and entorhinal cortex, and different anatomic markers can detect these neurotoxic effects to varying degrees. Here we report effects of domoic acid administration on quantitative indicators of brain metabolism and gliosis. Domoic acid, 2.25 mg/kg i.p., caused stereotyped behavior and convulsions in approximately 60% of rats which received it. Six to eight days after domoic acid or vehicle administration, the animals were processed to measure regional brain incorporation of the long-chain fatty acids [1-(14)C]arachidonic acid ([14C]AA) and [9,10-(3)H]palmitic acid ([3H]PA), or regional cerebral glucose utilization (rCMRglc) using 2-[1-(14)C]deoxy-D-glucose, by quantitative autoradiography. Others rats were processed to measure brain glial fibrillary acidic protein (GFAP) by enzyme-linked immunosorbent assay. Domoic acid increased GFAP in the anterior portion of cerebral cortex, the caudate putamen and thalamus compared with vehicle. However, in rats that convulsed after domoic acid GFAP was significantly increased throughout the cerebral cortex, as well as in the hippocampus, septum, caudate putamen, and thalamus. Domoic acid, in the absence of convulsions, decreased relative [14C]AA incorporation in the claustrum and pyramidal cell layer of the hippocampus compared with vehicle-injected controls. In the presence of convulsions, relative [14C]AA incorporation was decreased in hippocampus regions CA1 and CA2. Uptake of [3H]PA into brain was unaffected. Relative rCMRglc decreased in entorhinal cortex following domoic acid administration with or without convulsions. These results suggest that acute domoic acid exposure affects discrete brain circuits by inducing convulsions, and that domoic acid-induced convulsions cause chronic effects on brain function that are reflected in altered fatty acid metabolism and gliosis.
Appel
N M
NM
Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708-2476, USA. appeln@cder.fda.gov
Rapoport
S I
SI
O'Callaghan
J P
JP
Bell
J M
JM
Freed
L M
LM
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001345:Autoradiography; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002250:Carbon Radioisotopes; D003847:Deoxyglucose / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007263:Infusions, Parenteral; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D009928:Organ Specificity; D019308:Palmitic Acid / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012640:Seizures / Q000139:chemically induced / Q000473:pathology; D014316:Tritium
D015415:Biomarkers; D002250:Carbon Radioisotopes; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D014316:Tritium; D016718:Arachidonic Acid; D019308:Palmitic Acid; D003847:Deoxyglucose; D005947:Glucose; C012301:domoic acid; D007608:Kainic Acid