title: Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI.
abstract: Manganese (Mn(2+)) has limited permeability through the blood-brain barrier (BBB). Opening the BBB such that a sufficient amount of Mn(2+) enters the extracellular space is a critical step for dynamic manganese-enhanced magnetic resonance imaging (ME-MRI) experiments. The traditional BBB opening method uses intracarotid hyperosmolar stress which results in suboptimal BBB opening, and practically is limited to nonsurvival experiments due to substantial surgical trauma. In the present ME-MRI study, we investigate the feasibility of opening the BBB with an antibody that targets the endothelial barrier antigen (EBA) specifically expressed by rat endothelial cells. Results demonstrate that intravenous infusion of the anti-EBA agent SMI-71 leads to BBB disruption of the whole brain as detected by ME-MRI and confirmed by Evans blue dye staining. Physiologically, injection of SMI-71 leads to a hypertensive response followed by a sustained hypotensive response in animals anesthetized with urethane alone. Incorporating isoflurane partially mitigated both pressor responses. In general, BBB disruption via intravenous infusion of SMI-71 is straightforward and obviates technical difficulties associated with intracarotid hyperosmolar stress, opening new possibilities for in vivo neuroimaging with ME-MRI. The data also suggest that ME-MRI may be used as an imaging method to assess BBB integrity complementary to the Evans blue dye method, a classical but highly invasive technique, permitting longitudinal assessment of the integrity of the BBB on the same animal.
authors.affiliation: Neuroimaging Research Branch, National Institute on Drug Abuse, NIH, 251 Bayview Blvd, Suite 200, Rm 7A711, Baltimore, MD 21224, USA.
authors.forename: Hanbing
authors.initials: H
authors.lastname: Lu
authors.forename: Steven
authors.initials: S
authors.lastname: Demny
authors.forename: Yantao
authors.initials: Y
authors.lastname: Zuo
authors.forename: William
authors.initials: W
authors.lastname: Rea
authors.forename: Leiming
authors.initials: L
authors.lastname: Wang
authors.forename: Svetlana I
authors.initials: SI
authors.lastname: Chefer
authors.forename: D Bruce
authors.initials: DB
authors.lastname: Vaupel
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yang
authors.forename: Elliot A
authors.initials: EA
authors.lastname: Stein
mesh_terms: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000954:Antigens, Surface / Q000276:immunology*; D001794:Blood Pressure; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology; D004396:Coloring Agents; D003287:Contrast Media; D004347:Drug Interactions; D005070:Evans Blue; D005240:Feasibility Studies; D007530:Isoflurane; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014520:Urethane
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D004396:Coloring Agents; D003287:Contrast Media; C114781:endothelial barrier antigen, rat; D014520:Urethane; D008345:Manganese; D005070:Evans Blue; D007530:Isoflurane