title: A moderate metal-binding hydrazone meets the criteria for a bioinorganic approach towards Parkinson's disease: Therapeutic potential, blood-brain barrier crossing evaluation and preliminary toxicological studies.
abstract: Alzheimer's and Parkinson's diseases share similar amyloidogenic mechanisms, in which metal ions might play an important role. In this last neuropathy, misfolding and aggregation of α-synuclein (α-Syn) are crucial pathological events. A moderate metal-binding compound, namely, 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ), which was previously reported as a potential 'Metal-Protein Attenuating Compound' for Alzheimer's treatment, is well-tolerated by healthy Wistar rats and does not alter their major organ weights, as well as the tissues' reduced glutathione and biometal levels, at a concentration of 200mgkg-1. INHHQ definitively crosses the blood-brain barrier and can be detected in the brain of rats so late as 24h after intraperitoneal administration. After 48h, brain clearance is complete. INHHQ is able to disrupt, in vitro, anomalous copper-α-Syn interactions, through a mechanism probably involving metal ions sequestering. This compound is non-toxic to H4 (human neuroglioma) cells and partially inhibits intracellular α-Syn oligomerization. INHHQ, thus, shows definite potential as a therapeutic agent against Parkinson's as well.
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Daphne Schneider
authors.initials: DS
authors.lastname: Cukierman
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: Pinheiro
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Sergio L P
authors.initials: SL
authors.lastname: Castiñeiras-Filho
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Anastácia Sá P
authors.initials: AS
authors.lastname: da Silva
authors.affiliation: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Rosario S2002LRK, Argentina.
authors.forename: Marco C
authors.initials: MC
authors.lastname: Miotto
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Anna
authors.initials: A
authors.lastname: De Falco
authors.affiliation: Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
authors.forename: Thales
authors.initials: T
authors.lastname: de P Ribeiro
authors.affiliation: Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maisonette
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Alessandra L M C
authors.initials: AL
authors.lastname: da Cunha
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Hauser-Davis
authors.affiliation: Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Landeira-Fernandez
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil.
authors.forename: Ricardo Q
authors.initials: RQ
authors.lastname: Aucélio
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
authors.forename: Marcos D
authors.initials: MD
authors.lastname: Pereira
authors.affiliation: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Rosario S2002LRK, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.affiliation: Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil. Electronic address: nicoarey@puc-rio.br.
authors.forename: Nicolás A
authors.initials: NA
authors.lastname: Rey
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002614:Chelating Agents; D006835:Hydrazones
keywords: Copper; MPAC; Metal hypothesis; Parkinson's disease; Wistar rats; α-Synuclein