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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

Lookup NU author(s): Professor Tiago Outeiro

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Abstract

© 2017 Elsevier Inc. 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 200 mg kg− 1. INHHQ definitively crosses the blood-brain barrier and can be detected in the brain of rats so late as 24 h after intraperitoneal administration. After 48 h, 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.


Publication metadata

Author(s): Cukierman DS, Pinheiro AB, Castiñeiras-Filho SLP, da Silva ASP, Miotto MC, De Falco A, de P Ribeiro T, Maisonette S, da Cunha ALMC, Hauser-Davis RA, Landeira-Fernandez J, Aucélio RQ, Outeiro TF, Pereira MD, Fernández CO, Rey NA

Publication type: Article

Publication status: Published

Journal: Journal of Inorganic Biochemistry

Year: 2017

Volume: 170

Pages: 160-168

Print publication date: 01/05/2017

Online publication date: 22/02/2017

Acceptance date: 20/02/2017

ISSN (print): 0162-0134

ISSN (electronic): 1873-3344

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jinorgbio.2017.02.020

DOI: 10.1016/j.jinorgbio.2017.02.020

PubMed id: 28249224


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