Neurotoxicity after intracarotid 1,3-bis(2-chloroethyl)-1-nitrosourea administration in the rat: hemodynamic changes studied by double-tracer autoradiography.
Changes in blood-brain (BBB) permeability and local cerebral blood flow after intracarotid administration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were examined quantitatively in rats with double-tracer autoradiography using [14C]alpha-amino-isobutyric acid and [18F]fluoroantipyrine. Forty-eight female Wistar rats were divided into four groups. The control group (Group 1) received 1 ml of 5% dextrose. The other three groups received three different doses of BCNU dissolved in 5% dextrose: Group II rats received 1 mg, Group III 3 mg, and Group IV 10 mg. The tracer study was performed on Day 1 or Days 4 to 12 after intracarotid administration of BCNU. In 11 rats in Group II, there were no changes of BBB permeability. Transient BBB permeability changes were seen in the striatum or hippocampus in 3 of the 5 rats (60%) in Group III within 24 hours. In 8 of 9 rats (89%) in the same group, late BBB permeability changes were observed in the hypothalamus with or without histological changes. BBB permeability changes were seen in all rats of Group IV. Focal increase of local cerebral blood flow on the infused side compared with the non-infused side of the brain was observed, although not at a significant level, in 5 of 25 rats examined with [18F]fluoroantipyrine. The results of BBB permeability and histological examinations and study of heterogenous distribution by [18F]fluorodeoxyglucose indicated that the ipsilateral subcortical structures such as the hypothalamus, amygdala, internal capsule, and caudate putamen have the highest incidence of neurotoxicity, which are closely related to histopathological damage seen in human BCNU leucoencephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Nagahiro
S
S
Cone Laboratory for Neurosurgical Research, Montreal Neurological Institute, Quebec, Canada.
Yamamoto
Y L
YL
Diksic
M
M
Mitsuka
S
S
Sugimoto
S
S
Feindel
W
W
D000613:Aminobutyrates / Q000493:pharmacokinetics; D000679:Amygdala / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002250:Carbon Radioisotopes; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002339:Carotid Arteries; D002421:Caudate Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D005260:Female; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D006624:Hippocampus / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007269:Injections, Intra-Arterial; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D013788:Thalamus / Q000378:metabolism; D014018:Tissue Distribution
D000613:Aminobutyrates; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; C012223:alpha-aminobutyric acid; D003847:Deoxyglucose; D000983:Antipyrine; D002330:Carmustine