Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced cytotoxicity in Parkinson's disease in vitro models.
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 alpha-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.
Outeiro
Tiago Fleming
TF
Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg. 114-3300, 16th St., Charlestown, MA 02129-4404, USA. touteiro@gmail.com
Grammatopoulos
Tom N
TN
Altmann
Steven
S
Amore
Allison
A
Standaert
David G
DG
Hyman
Bradley T
BT
Kazantsev
Aleksey G
AG
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051844:alpha-Synuclein / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051844:alpha-Synuclein; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine