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.

Autor: Cukierman DS; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Pinheiro AB; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Castiñeiras-Filho SL; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., da Silva AS; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Miotto MC; 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., De Falco A; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., de P Ribeiro T; Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Maisonette S; Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., da Cunha AL; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Hauser-Davis RA; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Landeira-Fernandez J; Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Aucélio RQ; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil., Outeiro TF; Department of Neurodegeneration and Restorative Research, University Medical Center Goettingen, Goettingen, Germany., Pereira MD; Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil., Fernández CO; 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., Rey NA; Department of Chemistry, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro 22451-900, Brazil. Electronic address: nicoarey@puc-rio.br.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2017 May; Vol. 170, pp. 160-168. Date of Electronic Publication: 2017 Feb 22.
DOI: 10.1016/j.jinorgbio.2017.02.020
Abstrakt: 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.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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