Effect of an anticholinesterase compound on the ultrastructure and function of the rat blood-brain barrier: a review and experiment.
Soman, an organophosphorous irreversible inhibitor of acetylcholinesterase, was studied for its effect on the rat blood-brain barrier (BBB) during the first 24 h of intoxication. Young adult male Sprague-Dawley rats, injected with Evans blue-dye and surviving a subsequent single convulsive dose of soman (114 micrograms/kg, 0.9LD50), presented focal and diffuse penetration of dye in areas of brain normally considered protected by the BBB. Invasion was widest during the first hour when signs of excitation, respiratory distress and convulsions peaked and was absent at 24 h. During this time period, cholinesterase inhibition, as measured by enzyme assay, persisted in brain and blood at 10% and 6% of control values respectively. Brains of nonconvulsing animals and animals pretreated with nembutal (45 mg/kg, I.P.) or with diazepam (10 mg/kg, I.P.) were free of extravasated dye. A ranking of dye-breached brain areas suggested that cerebellar and cerebral cortex were most frequently involved while brain stem was rarely stained. Ultrastructural analysis of breached areas with horseradish peroxidase as a tracer molecule, revealed that the probable subcellular mechanism of the induced breach was enhanced vesicular transport, a mechanism similarly described for seizure. Consequences of the breach were emphasized with the detection of significantly elevated levels of an exogenously administered quaternary compound, 3H-hexamethonium. These findings present additional evidence that an anticholinesterase-induced breach of the rat blood-brain barrier is convulsive dependent, demonstrates BBB mechanisms similar to that of seizure, and can allow CNS penetration of blood-borne drugs and circulatory proteins that normally would be slowed or excluded by an intact BBB.(ABSTRACT TRUNCATED AT 250 WORDS)
Petrali
J P
JP
Comparative Pathology Branch, USAMRICD, Aberdeen Proving Ground.
Maxwell
D M
DM
Lenz
D E
DE
Mills
K R
KR
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D006584:Hexamethonium Compounds / Q000032:analysis / Q000494:pharmacology; D006735:Horseradish Peroxidase; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D012999:Soman / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D006584:Hexamethonium Compounds; D012999:Soman; D006735:Horseradish Peroxidase; D010424:Pentobarbital; D003975:Diazepam