Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy

Olga Ilnytska, Valeriy V. Lyzogubov, Martin J. Stevens, Viktor R. Drel, Nazar Mashtalir, Pal Pacher, Mark A. Yorek, Irina G. Obrosova

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg·kg-1·day-1 i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADP-ribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.

Original languageEnglish (US)
Pages (from-to)1686-1694
Number of pages9
JournalDiabetes
Volume55
Issue number6
DOIs
StatePublished - 2006

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Keywords

  • DRG, dorsal root ganglia
  • ISO, 1,5-isoquinolinediol
  • PARP, poly(ADP-ribose) polymerase
  • STZ, streptozotocin
  • TUNEL, transferase-mediated dUTP nick-end labeling

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