title: Ascorbic and 6-Br-ascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs.
abstract: Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [(14)C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice.
authors.affiliation: Department of Pharmaceutical Sciences, Ferrara University, via Fossato di Mortara 19, 44100 Ferrara, Italy. dla@dns.unife.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: Barbara
authors.initials: B
authors.lastname: Pavan
authors.forename: Silvia
authors.initials: S
authors.lastname: Vertuani
authors.forename: Federica
authors.initials: F
authors.lastname: Vitali
authors.forename: Martina
authors.initials: M
authors.lastname: Scaglianti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bortolotti
authors.forename: Carla
authors.initials: C
authors.lastname: Biondi
authors.forename: Angelo
authors.initials: A
authors.lastname: Scatturin
authors.forename: Sergio
authors.initials: S
authors.lastname: Tanganelli
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.forename: Giuliano
authors.initials: G
authors.lastname: Marzola
authors.forename: Puttur
authors.initials: P
authors.lastname: Prasad
authors.forename: Stefano
authors.initials: S
authors.lastname: Manfredini
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000378:metabolism / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D051379:Mice; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D002491:Central Nervous System Agents; C068572:6-deoxy-6-bromoascorbic acid; D001205:Ascorbic Acid