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

https://doi.org/10.1016/j.freeradbiomed.2007.09.013Get rights and content

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.

Section snippets

Reagents

Unless otherwise stated, all chemicals were of reagent-grade quality and were purchased from Sigma Chemical Co. (St. Louis, MO, USA). The PARP inhibitor GPI-15427 (formulated as a mesilate salt) was synthesized by MGI Pharma. Mouse monoclonal anti-poly(ADP-ribose) was obtained from Trevigen, Inc. (Gaithersburg, MD, USA). Secondary Alexa Fluor 488 goat anti-rabbit and Alexa Fluor 488 goat anti-mouse antibodies, secondary FITC–rabbit anti-goat IgG (H + L) as well as Prolong Gold Antifade Reagent

Results

The final body weights were similarly reduced and the final blood glucose concentrations similarly elevated in untreated and GPI-15427-treated diabetic rats compared with the control group (Table 1). PARP inhibition did not affect either weight gain or blood glucose concentrations in nondiabetic rats. Weight gain was similar in nondiabetic wild-type and PARP−/− mice and was lower in diabetic PARP+/+ and diabetic PARP−/− mice than in corresponding untreated groups. Diabetic PARP−/− mice, but not

Discussion

Evidence that oxidative–nitrosative stress plays an important role in small sensory fiber neuropathy, a devastating complication of diabetes mellitus that culminates in total sensation loss and is responsible for foot amputation [25], is emerging [26], [27], [28]. We have recently reported that peroxynitrite decomposition catalysts, at a very low dose of 5–10 mg kg 1 day 1, alleviated small sensory nerve fiber dysfunction and degeneration [29], [30], [31]. The present study suggests that free

Acknowledgments

The study was supported by Juvenile Diabetes Research Foundation International Grant 1-2005-223, American Diabetes Association Research Grant 7-05-RA-102, and National Institutes of Health Grant DK 071566-01 (all to I.G.O.). Drs. Weizheng Xu, Jie Zhang, and Barbara Slusher are employed by MGI Pharma, the company developing PARP inhibitors, and thus have a potential conflict of interest. The authors thank Jeho Shin for expert technical assistance.

References (43)

  • P. Jagtap et al.

    Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors

    Nat. Rev. Drug Discovery

    (2005)
  • F. Garcia Soriano et al.

    Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation

    Nat. Med.

    (2001)
  • P. Pacher et al.

    The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes

    Diabetes

    (2002)
  • I.G. Obrosova et al.

    Role of poly(ADP-ribose) polymerase activation in diabetic neuropathy

    Diabetes

    (2004)
  • F. Li et al.

    Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

    Diabetologia

    (2004)
  • L. Zheng et al.

    Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB

    Diabetes

    (2004)
  • I.G. Obrosova et al.

    Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression

    Int. J. Mol. Med.

    (2004)
  • A.G. Minchenko et al.

    Diabetes-induced overexpression of endothelin-1 and endothelin receptors in the rat renal cortex is mediated via poly(ADP-ribose) polymerase activation

    FASEB J.

    (2003)
  • C. Szabo et al.

    Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice

    Diabetes

    (2006)
  • A.K. Cheung et al.

    Aldose reductase deficiency prevents diabetes-induced blood–retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice

    Diabetes

    (2005)
  • V.R. Drel et al.

    The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity

    Diabetes

    (2006)
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