PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy

Irina G. Obrosova, Weizheng Xu, Valeriy V. Lyzogubov, Olga Ilnytska, Nazar Mashtalir, Igor Vareniuk, Ivan A. Pavlov, Jie Zhang, Barbara Slusher, Viktor R. Drel

Research output: Contribution to journalArticle

Abstract

Evidence that poly(ADP-ribose) polymerase (PARP) activation plays an important role in diabetic complications is emerging. This study evaluated the role of PARP in rat and mouse models of advanced diabetic neuropathy. The orally active PARP inhibitor 10-(4-methylpiperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15427; formulated as a mesilate salt, 30 mg kg- 1 day- 1 in the drinking water for 10 weeks after the first 2 weeks without treatment) at least partially prevented PARP activation in peripheral nerve and DRG neurons, as well as thermal hypoalgesia, mechanical hyperalgesia, tactile allodynia, exaggerated response to formalin, and, most importantly, intraepidermal nerve fiber degeneration in streptozotocin-diabetic rats. These findings are consistent with the lack of small sensory nerve fiber dysfunction in diabetic PARP-/- mice. Furthermore, whereas diabetic PARP+/+ mice displayed ∼ 46% intraepidermal nerve fiber loss, diabetic PARP-/- mice retained completely normal intraepidermal nerve fiber density. In conclusion, PARP activation is an important contributor to intraepidermal nerve fiber degeneration and functional changes associated with advanced Type 1 diabetic neuropathy. The results support a rationale for the development of potent and low-toxicity PARP inhibitors and PARP inhibitor-containing combination therapies.

Original languageEnglish (US)
Pages (from-to)972-981
Number of pages10
JournalFree Radical Biology and Medicine
Volume44
Issue number6
DOIs
StatePublished - Mar 15 2008
Externally publishedYes

Fingerprint

Poly(ADP-ribose) Polymerases
Diabetic Neuropathies
Neuralgia
Nerve Fibers
Genes
Fibers
Nerve Degeneration
Chemical activation
Hyperalgesia
Rats
Mesylates
Diagnosis-Related Groups
Diabetes Complications
Streptozocin
Peripheral Nerves
Drinking Water
Formaldehyde
Neurons
Toxicity
Salts

Keywords

  • Free radicals
  • Intraepidermal nerve fiber loss
  • Mechanical hyperalgesia
  • Mechanical hypoalgesia
  • Neuropathic pain
  • Oxidative-nitrosative stress
  • Poly(ADP-ribose) polymerase
  • Tactile allodynia
  • Thermal hypoalgesia

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. / Obrosova, Irina G.; Xu, Weizheng; Lyzogubov, Valeriy V.; Ilnytska, Olga; Mashtalir, Nazar; Vareniuk, Igor; Pavlov, Ivan A.; Zhang, Jie; Slusher, Barbara; Drel, Viktor R.

In: Free Radical Biology and Medicine, Vol. 44, No. 6, 15.03.2008, p. 972-981.

Research output: Contribution to journalArticle

Obrosova, Irina G. ; Xu, Weizheng ; Lyzogubov, Valeriy V. ; Ilnytska, Olga ; Mashtalir, Nazar ; Vareniuk, Igor ; Pavlov, Ivan A. ; Zhang, Jie ; Slusher, Barbara ; Drel, Viktor R. / PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. In: Free Radical Biology and Medicine. 2008 ; Vol. 44, No. 6. pp. 972-981.
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AU - Obrosova, Irina G.

AU - Xu, Weizheng

AU - Lyzogubov, Valeriy V.

AU - Ilnytska, Olga

AU - Mashtalir, Nazar

AU - Vareniuk, Igor

AU - Pavlov, Ivan A.

AU - Zhang, Jie

AU - Slusher, Barbara

AU - Drel, Viktor R.

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N2 - Evidence that poly(ADP-ribose) polymerase (PARP) activation plays an important role in diabetic complications is emerging. This study evaluated the role of PARP in rat and mouse models of advanced diabetic neuropathy. The orally active PARP inhibitor 10-(4-methylpiperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15427; formulated as a mesilate salt, 30 mg kg- 1 day- 1 in the drinking water for 10 weeks after the first 2 weeks without treatment) at least partially prevented PARP activation in peripheral nerve and DRG neurons, as well as thermal hypoalgesia, mechanical hyperalgesia, tactile allodynia, exaggerated response to formalin, and, most importantly, intraepidermal nerve fiber degeneration in streptozotocin-diabetic rats. These findings are consistent with the lack of small sensory nerve fiber dysfunction in diabetic PARP-/- mice. Furthermore, whereas diabetic PARP+/+ mice displayed ∼ 46% intraepidermal nerve fiber loss, diabetic PARP-/- mice retained completely normal intraepidermal nerve fiber density. In conclusion, PARP activation is an important contributor to intraepidermal nerve fiber degeneration and functional changes associated with advanced Type 1 diabetic neuropathy. The results support a rationale for the development of potent and low-toxicity PARP inhibitors and PARP inhibitor-containing combination therapies.

AB - Evidence that poly(ADP-ribose) polymerase (PARP) activation plays an important role in diabetic complications is emerging. This study evaluated the role of PARP in rat and mouse models of advanced diabetic neuropathy. The orally active PARP inhibitor 10-(4-methylpiperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15427; formulated as a mesilate salt, 30 mg kg- 1 day- 1 in the drinking water for 10 weeks after the first 2 weeks without treatment) at least partially prevented PARP activation in peripheral nerve and DRG neurons, as well as thermal hypoalgesia, mechanical hyperalgesia, tactile allodynia, exaggerated response to formalin, and, most importantly, intraepidermal nerve fiber degeneration in streptozotocin-diabetic rats. These findings are consistent with the lack of small sensory nerve fiber dysfunction in diabetic PARP-/- mice. Furthermore, whereas diabetic PARP+/+ mice displayed ∼ 46% intraepidermal nerve fiber loss, diabetic PARP-/- mice retained completely normal intraepidermal nerve fiber density. In conclusion, PARP activation is an important contributor to intraepidermal nerve fiber degeneration and functional changes associated with advanced Type 1 diabetic neuropathy. The results support a rationale for the development of potent and low-toxicity PARP inhibitors and PARP inhibitor-containing combination therapies.

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