Permeability changes in response to NONOate and NONOate prodrug derived nitric oxide in a blood-brain barrier model formed by primary porcine endothelial cells.
The influence of nitric oxide (NO) and NO-donors on the permeability of the blood-brain barrier (BBB) is still not well understood and the literature about this is quite controversial. Some studies suggest increasing, others decreasing or even no effects of NO-donors on the BBB permeability. In this work we report about the influence of three diazeniumdiolates, which release NO spontaneously and three different diazeniumdiolate prodrugs, which have to be cleaved chemically or enzymatically before releasing NO, on the permeability of an in vitro BBB-model formed by primary porcine endothelial cells. By measuring the flux of a small polar molecule (carboxyfluorescein: CF) we could show, that the NO-releasers PHEPIPERAZI/NO (sodium 1-(phenylpiperazin-1-yl)diazen-1-ium-1,2-diolate), DBA/NO (sodium 1-(N,N-dibutylamino)diazen-1-ium-1,2-diolate) and DETA/NO (1-N,N-di-(2-aminoethyl)amino)diazen-1-ium-1,2-diolate) reduced the BBB-model permeability. In contrast, the NO-prodrugs Et-PHEPIPERAZI/NO (O(2)-Ethyl-1-(phenylpiperazin-1-yl)diazen-1-ium-1,2-diolate) and TOSYL-PYRRO/NO (O(2)-(p-Methylbenzen-sulfonyl)-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate) increased the permeability in all investigated concentrations, whereas the prodrug Et-BUPIPERAZI/NO (O(2)-Ethyl-1-(butylpiperazin-1-yl)diazen-1-ium-1,2-diolate) reduced it at the lowest investigated concentration of 100 microM, at the higher concentrations it increased the permeability. Blocking the effect of the BBB-model permeability reducing compounds could be done by methylene blue, whereas permeability increasing effects could not be blocked.
Winter
Sven
S
Friedrich-Schiller-University Jena, Department of Pharmaceutical Technology, Lessingstrasse 8, 07743 Jena, Germany.
Konter
Joerg
J
Scheler
Stefan
S
Lehmann
Jochen
J
Fahr
Alfred
A
D000818:Animals; D001391:Azo Compounds / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D008751:Methylene Blue / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors
D001391:Azo Compounds; D005456:Fluorescent Dyes; D020030:Nitric Oxide Donors; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D008751:Methylene Blue