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