title: A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.
abstract: BACKGROUND
  Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.
  
  
  RESULTS
  An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.
  
  
  CONCLUSIONS
  Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.
authors: Department of Neurology, Mayo Clinic, College of Medicine, Rochester, Minnesota, United States of America. ta.lauren@mayo.edu
authors: Lauren E
authors: LE
authors: Ta
authors: James D
authors: JD
authors: Schmelzer
authors: Allan J
authors: AJ
authors: Bieber
authors: Charles L
authors: CL
authors: Loprinzi
authors: Gary C
authors: GC
authors: Sieck
authors: Jill D
authors: JD
authors: Brederson
authors: Philip A
authors: PA
authors: Low
authors: Anthony J
authors: AJ
authors: Windebank
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis; D002945:Cisplatin / Q000633:toxicity; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009944:Organoplatinum Compounds / Q000633:toxicity; D000077150:Oxaliplatin; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018696:Neuroprotective Agents; D009944:Organoplatinum Compounds; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000077150:Oxaliplatin; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin