A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy

Lauren E. Ta, James D. Schmelzer, Allan J. Bieber, Charles Lawrence Loprinzi, Gary C Sieck, Jill D. Brederson, Phillip Anson Low, Anthony John Windebank

Research output: Contribution to journalArticle

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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. Conclusion: 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.

Original languageEnglish (US)
Article numbere54161
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 17 2013

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oxaliplatin
NAD ADP-ribosyltransferase
Chemotherapy
peripheral nervous system diseases
Hyperalgesia
cisplatin
Cisplatin
drug therapy
Drug Therapy
heat
pain
mice
Drug therapy
Poly(ADP-ribose) Polymerases
Hot Temperature
Testing
Platinum
therapeutics
platinum
testing

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy. / Ta, Lauren E.; Schmelzer, James D.; Bieber, Allan J.; Loprinzi, Charles Lawrence; Sieck, Gary C; Brederson, Jill D.; Low, Phillip Anson; Windebank, Anthony John.

In: PLoS One, Vol. 8, No. 1, e54161, 17.01.2013.

Research output: Contribution to journalArticle

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