title: WR-2721 entry into the brain across a modified blood-brain barrier.
abstract: Radioprotection of the CNS by WR-2721 has not been possible because of its inability to cross the blood-brain barrier (BBB) and so gain access to the neural tissue. Modification of the BBB using hypertonic arabinose (1.8 m), injected via the internal carotid artery (ica), permitted entry of ip-injected [14C]WR-2721 into the ipsilateral cerebral hemisphere. The BBB-modified hemisphere had a 5.34-fold increased uptake compared to nonmodified controls. Delivery as a bolus via the ica further enhanced uptake after BBB opening; WR-2721 was 3.73 times greater than by ip injection. A 20-fold increase of WR-2721 brain uptake has been calculated for ica administration with the BBB opened as compared to the ip route without BBB modification. Toxicity of ip-administered WR-2721 with the BBB open was only 1.4 times greater than non-modified controls and 1.96 times more toxic when delivered via the ica. These data demonstrate significant uptake of WR-2721 into the CNS, a previously unprotected organ, and provide a model for future radioprotective studies.
authors.affiliation: Department of Anatomy, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
authors.forename: A
authors.initials: A
authors.lastname: Lamperti
authors.forename: A D
authors.initials: AD
authors.lastname: Conger
authors.forename: O
authors.initials: O
authors.lastname: Jenkins
authors.forename: G
authors.initials: G
authors.lastname: Cohen
authors.forename: A
authors.initials: A
authors.lastname: Rizzo
authors.forename: M E
authors.initials: ME
authors.lastname: Davis
authors.forename: M
authors.initials: M
authors.lastname: Sodicoff
mesh_terms: D004999:Amifostine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001089:Arabinose / Q000008:administration & dosage / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002339:Carotid Arteries; D005070:Evans Blue; D005260:Female; D006982:Hypertonic Solutions; D007261:Infusions, Intra-Arterial; D007269:Injections, Intra-Arterial; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D006982:Hypertonic Solutions; D009946:Organothiophosphorus Compounds; D005070:Evans Blue; D001089:Arabinose; D004999:Amifostine