Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson's Disease

Mol Neurobiol. 2021 Aug;58(8):3641-3652. doi: 10.1007/s12035-021-02371-4. Epub 2021 Mar 31.

Abstract

Repurposing PARP-1 inhibitors (PARPi) for non-oncological applications offers an attractive therapeutic strategy for pathological conditions characterized by PARP-1 hyperactivity. In the context of Parkinson's disease (PD), PARP-1 hyperactivity has been linked to neuronal death and disease progression. From a therapy perspective, the evaluation of PARPi as neuroprotective agents may offer a new therapeutic alternative for neurodegenerative disorders. An ideal PARPi needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage and cellular toxicity-an effect that is attractive in cancer but far from ideal in neurological disease applications. Consequently, in this study, we set out to evaluate the neuroprotective properties of a previously reported low-toxicity PARPi (10e) using in vitro neuronal models of PD. 10e is a structural analogue of FDA-approved PARPi olaparib, with high PARP-1 affinity and selectivity. Our studies revealed that 10e protects neuronal cells from oxidative stress and DNA damage. In addition, 10e exhibits neuroprotective properties against α-synuclein pre-formed fibrils (αSyn PFF) mediated effects, including reduction in the levels of phosphorylated αSyn and protection against abnormal changes in NAD+ levels. Our in vitro studies with 10e provide support for repurposing high-affinity and low-toxicity PARPi for neurological applications and lay the groundwork for long-term therapeutic studies in animal models of PD.

Keywords: Alpha-synuclein; Nicotinamide adenine dinucleotide; PARP inhibitor; Parkinson’s disease; Poly(ADP-ribose); Poly(ADP-ribose) polymerase-1; Pre-formed fibrils.

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Gene Knockout Techniques / methods
  • Humans
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Neuroprotective Agents / toxicity
  • Parkinson Disease / metabolism
  • Parkinson Disease / prevention & control*
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use
  • Phthalazines / toxicity
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Piperazines / toxicity
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors / toxicity

Substances

  • Neuroprotective Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • olaparib