New hydroxypyridinone iron-chelators as potential anti-neurodegenerative drugs.
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 Abeta(1-40) and/or Abeta(1-42) peptides. Our results show that all these compounds improved cell viability in cells treated with MPP+ and Abeta(1-40) peptide or Abeta(1-42) 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.
Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, 3030 Coimbra, Portugal.
Daniela
D
Arduino
Daniel
D
Silva
Sandra M
SM
Cardoso
Silvia
S
Chaves
Catarina R
CR
Oliveira
M Amelia
MA
Santos
D045744:Cell Line, Tumor; D006801:Humans; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D010300:Parkinson Disease / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D018243:Teratocarcinoma
D007502:Iron Chelating Agents; D010879:Piperazines; D011725:Pyridines; D011728:Pyridones; C014047:hydroxypyridines