title: Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions.
abstract: We report for the first time on neuronal signaling for the evaluation of interactions between native plasmamembrane and polyamidoamine (PAMAM) dendrimers. Generation 5 polycationic (G5-NH(2)), novel β-D-glucopyranose-conjugated G5-NH(2) and generation 4.5 polyanionic (G4.5-COONa) polyamidoamine (PAMAM) dendrimers (1-0.0001 mg/ml) were applied in acute brain slices. Functional toxicity assessments-validated by fluorescence imaging of dead cells-were performed by employing electrophysiological indicators of plasma membrane breakdown and synaptic transmission relapse. Irreversible membrane depolarization and decrease of membrane resistance predicted substantial functional neurotoxicity of unmodified G5-NH(2), but not of the G4.5-COONa PAMAM dendrimers. Model calculations suggested that freely moving protonated NH(2) groups of terminal monomeric units of PAMAM dendrimers may be able directly destroy the membrane or inhibit important K(+) channel function via contacting the positively charged NH(2). In accordance, conjugation of surface amino groups by β-D-glucopyranose units reduced functional neurotoxicity that may hold great potential for biomedical applications.
authors.affiliation: Department of Neurochemistry, Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy, Budapest, Hungary. nyitraig@chemres.hu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nyitrai
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kékesi
authors.forename: Ildikó
authors.initials: I
authors.lastname: Pál
authors.forename: Péter
authors.initials: P
authors.lastname: Keglevich
authors.forename: Zsuzsánna
authors.initials: Z
authors.lastname: Csíki
authors.forename: Péter
authors.initials: P
authors.lastname: Fügedi
authors.forename: Agnes
authors.initials: A
authors.lastname: Simon
authors.forename: Ilona
authors.initials: I
authors.lastname: Fitos
authors.forename: Krisztina
authors.initials: K
authors.lastname: Németh
authors.forename: Júlia
authors.initials: J
authors.lastname: Visy
authors.forename: Gábor
authors.initials: G
authors.lastname: Tárkányi
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry / Q000633:toxicity*; D005456:Fluorescent Dyes / Q000032:analysis; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D050091:Dendrimers; D005456:Fluorescent Dyes; D009498:Neurotoxins; C104700:PAMAM Starburst; D005947:Glucose