title: Ability of carbazole salts, inhibitors of Alzheimer beta-amyloid fibril formation, to cross cellular membranes.
abstract: Alzheimer's disease is characterized by the presence of beta-amyloid fibril formation. The inhibition of this peptide accumulation may be a prevention method for Alzheimer's disease. Several classes of molecules have been reported to inhibit beta-amyloid fibril formation and among them carbazoles. However, very few studies have been performed to determine the destination of such molecules in vivo and especially if they can pass the blood brain barrier. The aim of this paper is to study whether carbazoles could pass the blood brain barrier, i.e. if they can circumvent ATP Binding Cassette (ABC) transporters such as P-glycoprotein (P-gp) and Multidrug Resistance-associated protein (MRP1) which efficiently limit drug brain uptake. For this purpose we have synthesized a fluorescent derivative of carbazole benzothiazolium iodide 1,2 disubstituted ethylene (referred as carbazole thiazole: CT), which can be easily detected and followed in the pre-trial study phases in cells or in tissue. We use cellular models overexpressing P-gp and MRP1. Our results show that: i) CT is able to cross membranes and to penetrate rapidly inside the cells, ii) CT is a P-gp substrate and consequently its accumulation in P-gp overexpressing cells is very low, iii) CT is a poor MRP1 substrate. In addition once inside the cells, CT rapidly binds to DNA and is then slowly reduced by intracellular reducing agents. In conclusion, the efficiency of carbazole derivatives in inhibiting the beta-amyloid formation in vivo could be highly compromised because, as P-gp substrates, they will probably not cross the blood brain barrier.
authors.affiliation: Laboratoire de Biophysique Moléculaire, Cellulaire et Tissulaire, UMR CNRS 7033, Université Paris 13 et Paris 6, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Chantarawan
authors.initials: C
authors.lastname: Saengkhae
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
authors.forename: Dominique
authors.initials: D
authors.lastname: Adès
authors.forename: Alain
authors.initials: A
authors.lastname: Siove
authors.forename: Laurence
authors.initials: L
authors.lastname: Le Moyec
authors.forename: Véronique
authors.initials: V
authors.lastname: Migonney
authors.forename: Arlette
authors.initials: A
authors.lastname: Garnier-Suillerot
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002942:Circular Dichroism; D003498:Cyclic P-Oxides / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008564:Membrane Potentials; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology; D010084:Oxidation-Reduction; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors; D014230:Triazoles / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D002227:Carbazoles; D003498:Cyclic P-Oxides; D004247:DNA; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009243:NAD; D009539:Nicotinic Acids; D014230:Triazoles; C103821:PAK 104P; C421109:multidrug resistance-associated protein 1