title: PARP inhibitors attenuate chemotherapy-induced painful neuropathy.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a major toxicity of chemotherapy treatment for which no therapy is approved. Poly(ADP-ribose) polymerase (PARP)1/2 are nuclear enzymes activated upon DNA damage, and PARP1/2 inhibition provides resistance against DNA damage. A role for PARP inhibition in sensory neurotransmission has also been established. PARP inhibitors attenuate pain-like behaviors and neuropathy-associated decreased peripheral nerve function in diabetic models. The hypothesis tested was that PARP inhibition protects against painful neuropathy. The objective of this study was to investigate whether the novel, selective PARP1/2 inhibitors (ABT-888 and related analogues) would attenuate development of mechanical allodynia in vincristine-treated rats. PARP inhibitors were dosed for 2 days, and then co-administered with vincristine for 12 days. Mechanical allodynia was observed in rats treated with vincristine. PARP1/2 inhibition significantly attenuated development of mechanical allodynia and reduced poly ADP-ribose (PAR) activation in rat skin. The data presented here show that PARP inhibition attenuates vincristine-induced mechanical allodynia in rats, and supports that PARP inhibition may represent a novel therapeutic approach for CIPN.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. jill-desiree.brederson@abbott.com
authors.forename: Jill-Desiree
authors.initials: JD
authors.lastname: Brederson
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Joseph
authors.initials: J
authors.lastname: Mikusa
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Donna
authors.initials: D
authors.lastname: Gauvin
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
authors.forename: Alex R
authors.initials: AR
authors.lastname: Shoemaker
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009437:Neuralgia / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C483041:PARP2 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases