IMR Press / FBL / Volume 13 / Issue 17 / DOI: 10.2741/3187

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Article
New hydroxypyridinone iron-chelators as potential anti-neurodegenerative drugs
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1 1 Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, 3030 Coimbra, Portugal
2 Centro Quimica Estrutural, Instituto Superior Tecnico-UTL, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
3 Instituto de Biologia, Faculdade de Medicina, Universidade de Coimbra, 3030 Coimbra, Portugal
4 Instituto de Bioquimica, Faculdade de Medicina, Universidade de Coimbra, 3030 Coimbra, Portugal

*Author to whom correspondence should be addressed.

 

Front. Biosci. (Landmark Ed) 2008, 13(17), 6763–6774; https://doi.org/10.2741/3187
Published: 1 May 2008
Abstract

The neuroprotective action of a set of new hydroxypyridinone-based (3,4-HP) compounds (A, B and C), which are iron chelators extra-functionalized with a propargylamino group for potential MAO-B inhibition, was evaluated after cell treatment with MPP+ (an in vivo inducer of parkinsonism) and Abeta1-40 and/or Abeta1-42 peptides. Our results show that all these compounds improved cell viability in cells treated with MPP+ and Abeta1-40 peptide or Abeta1-42 peptide. In order to evaluate the cellular mechanisms underlying the activity of these compounds, we studied their protective role in caspase activation. All compounds tested were able to prevent MPP+ and Brefeldin A induced caspase-2 activation. They also showed quite effective in the inhibition of caspase-4 and caspase-3 activity, an effector caspase in the apoptotic process. Finally, detection of apoptotic-like cell death after cell exposure to MPP+ was also performed by TUNEL assay. Our results demonstrated that all tested compounds prevented DNA fragmentation by decreasing TUNEL positive cells. A, B and C were more effective than DFP (a 3,4-HP iron-chelating agent in clinical use) in MPP+ induced cell death. Therefore, these results evidenced a neuroprotective and antiapoptotic role for the compounds studied.

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