title: Blood-brain barrier disruption using mannitol: time course and electron microscopy studies.
abstract: Blood-brain barrier disruption with a hyperosmolar agent, mannitol, has previously been demonstrated to increase intracerebral methotrexate levels in rats. To determine the optimum conditions for blood-brain barrier disruption without producing neurological sequelae, adult Sprague-Dawley rats were infused with mannitol via the internal carotid artery at rates varying from 0.25 to 0.5 ml.s-1.kg-1. Methotrexate and Evans blue were used as markers of blood-brain barrier disruption. The optimum rate of mannitol that produced blood-brain barrier disruption without neurological sequelae was 0.25 ml.s-1.kg-1 for 20 s. The duration of blood-brain barrier opening was maximal for approximately 5 min and then rapidly reversed. Methotrexate levels on the mannitol-infused side were four to five times that of the noninfused hemisphere. Light microscopy and electron microscopy did not demonstrate any consistent changes that could be attributed to blood-brain barrier disruption nor did it elucidate the mechanism. This model should prove useful in the investigation of the treatment of intracerebral tumors with blood-brain barrier disruption. This study shows that maximal intracerebral methotrexate levels were obtained when methotrexate was infused before or within 5 min of the mannitol infusion.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Austin Hospital, Heidelberg, Australia.
authors.forename: W C
authors.initials: WC
authors.lastname: Cosolo
authors.forename: P
authors.initials: P
authors.lastname: Martinello
authors.forename: W J
authors.initials: WJ
authors.lastname: Louis
authors.forename: N
authors.initials: N
authors.lastname: Christophidis
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000648:ultrastructure*; D002339:Carotid Arteries; D005070:Evans Blue; D008353:Mannitol / Q000494:pharmacology*; D008727:Methotrexate; D008854:Microscopy, Electron; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
chemical_list: D008353:Mannitol; D005070:Evans Blue; D008727:Methotrexate