Showing papers by "Sandra M. Cardoso published in 2008"
TL;DR: The authors' data support a relatively upstream role for mitochondrial dysfunction in idiopathic PD, and show that equivalent MPP+ exposures are more likely to trigger programmed cell death in PD cybrid cells than in control Cybrid cells.
103 citations
TL;DR: The results suggest that a mitochondrial alteration leads to an imbalance in the cellular oxidative status, inducing a proteasomal deregulation, which may exacerbate protein aggregation, and consequently degenerative events.
40 citations
TL;DR: A, B and C were more effective than DFP (a 3,4-HP iron-chelating agent in clinical use) in MPP+ induced cell death and evidenced a neuroprotective and antiapoptotic role for the compounds studied.
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 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.
16 citations
TL;DR: It is concluded that MPP-induced apoptosis requires functional mitochondria, MPP+ activates calpains independent of respiratory chain inhibition, and calpain activation mediates some aspects of MPP + toxicity.
Abstract: MPP+ (1-methyl-4-phenylpyridium ion), a complex I — inhibiting metabolite of 1-methyl-4-phe-nyl-1,2,3,6-tetrahydropyridine (MPTP), causes anatomic-specific neurodegeneration. To evaluate the broader role of mitochondria in MPP+- induced cell death, we exposed neuron-like NT2 human teratocarcinoma cells with mtDNA(rho+) and without mtDNA (rho0) to MPP+. MPP+ minimized the ability of both rho+ and rho0 cells to reduce MTT. Only rho+ cells, though, initiated intrinsic pathway-mediated apoptosis. MPP+ also activated calpains in rho0 cell lines. The calpain inhibitor MDL 28710 was able to prevent the MPP+-related MTT reduction change in rho0 but not rho+ cells. We conclude that 1) MPP+-induced apoptosis requires functional mitochondria, 2) MPP+ activates calpains independent of respiratory chain inhibition, and 3) calpain activation mediates some aspects of MPP+ toxicity.
15 citations