Pharmacological inhibition of PARP-1 reduces α-synuclein- and MPP+-induced cytotoxicity in Parkinson's disease in vitro models

Academic Article

Abstract

  • Treatments based on pharmacological inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) have been suggested for a broad variety of human disorders, including Parkinson's disease (PD). The neuroprotective effects underlying the efficacy of PARP-1 inhibitors in PD models suggest a role for PARP-1 in neurodegeneration. In this study, we assessed the efficacy of PARP-1 inhibition in two distinct PD models. First, we tested a panel of small molecule PARP-1 inhibitors in α-synuclein (aSyn) cytotoxicity assay, where we observed compound-dependent ameliorating effects. Next, we tested the same panel in primary ventral mesencephalic neuronal cultures, treated with MPP+. Dopaminergic neurons, the primary cells affected in PD, were selected and subjected to analysis. A significant ameliorating effect was achieved only with a highly potent PARP-1 inhibitor. Our data implicates aberrant PARP-1 function in different pathways of neurodegeneration. Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients. © 2007 Elsevier Inc. All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Outeiro TF; Grammatopoulos TN; Altmann S; Amore A; Standaert DG; Hyman BT; Kazantsev AG
  • Start Page

  • 596
  • End Page

  • 602
  • Volume

  • 357
  • Issue

  • 3