Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

Irina G. Obrosova, Fei Li, Omorodola I. Abatan, Mark A. Forsell, K. Komjáti, Pal Pacher, Csaba Szabó, Martin J. Stevens

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mechanisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP-/-) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP+/+) diabetic or galactose-fed mice. Two structurally unrelated PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induced diabetic rats. Sciatic nerve immunohistochemistry revealed enhanced poly(ADP-ribosyl)ation in all experimental groups manifesting neuropathic changes. Poly(ADP-ribose) accumulation was localized in both endothelial and Schwann cells. Thus, the current work identifies PARP activation as an important mechanism in diabetic neuropathy and provides the first evidence for the potential therapeutic value of PARP inhibitors in this devastating complication of diabetes.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalDiabetes
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 2004

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Poly(ADP-ribose) Polymerases
Diabetic Neuropathies
Galactose
Poly Adenosine Diphosphate Ribose
Schwann Cells
Neural Conduction
Sciatic Nerve
Diabetes Complications
Streptozocin
Oxidants
Adenosine Diphosphate
DNA Damage
Oxidative Stress
Endothelial Cells
Immunohistochemistry

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Obrosova, I. G., Li, F., Abatan, O. I., Forsell, M. A., Komjáti, K., Pacher, P., ... Stevens, M. J. (2004). Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy. Diabetes, 53(3), 711-720. https://doi.org/10.2337/diabetes.53.3.711

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy. / Obrosova, Irina G.; Li, Fei; Abatan, Omorodola I.; Forsell, Mark A.; Komjáti, K.; Pacher, Pal; Szabó, Csaba; Stevens, Martin J.

In: Diabetes, Vol. 53, No. 3, 03.2004, p. 711-720.

Research output: Contribution to journalArticle

Obrosova, IG, Li, F, Abatan, OI, Forsell, MA, Komjáti, K, Pacher, P, Szabó, C & Stevens, MJ 2004, 'Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy', Diabetes, vol. 53, no. 3, pp. 711-720. https://doi.org/10.2337/diabetes.53.3.711
Obrosova, Irina G. ; Li, Fei ; Abatan, Omorodola I. ; Forsell, Mark A. ; Komjáti, K. ; Pacher, Pal ; Szabó, Csaba ; Stevens, Martin J. / Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy. In: Diabetes. 2004 ; Vol. 53, No. 3. pp. 711-720.
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