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Diabetes 54:1514-1522, 2005
© 2005 by the American Diabetes Association, Inc.

Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy

Fei Li1, Viktor R. Drel2, Csaba Szabó3, Martin J. Stevens1, and Irina G. Obrosova1,2

1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
2 Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
3 Inotek Pharmaceuticals, Beverly, Massachusetts

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects. This study evaluated potential synergistic interactions between low doses of the potent and specific PARP inhibitor 1,5-isoquinolinediol (ISO) and one of two vasodilators, the ACE inhibitor lisinopril (LIS) and the ß2-adrenoceptor agonist salbutamol (SAL) in the model of early PDN. Control and streptozotocin (STZ)-induced diabetic rats were treated with either ISO plus LIS or ISO plus SAL for 2 weeks after an initial 2 weeks without treatment. ISO (intraperitoneally) and LIS and SAL (both in the drinking water) were used in subtherapeutic doses, resulting in a minor correction of diabetes-associated sciatic motor and hind-limb digital sensory nerve conduction deficits when administered as monotherapies. Both combination treatments corrected endoneurial blood flow and vascular conductance deficits in STZ-induced diabetic rats. ISO plus SAL corrected all other changes of PDN, i.e., motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) deficits as well as thermal and mechanical hyperalgesia. With ISO plus LIS, no significant correction of MNCV was observed, and the effect on thermal hyperalgesia was quite modest. SNCV and mechanical hyperalgesia were corrected. In vitro studies in human endothelial and Schwann cells showed early accumulation of poly(ADP-ribosyl)ated proteins (Western blot analysis) in response to high glucose, thus suggesting the importance of PARP activation in human PDN. In conclusion, low-dose PARP inhibitor-containing combination therapies may constitute a new approach for treatment of PDN.

Address correspondence and reprint requests to Irina G. Obrosova, PhD, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd., Baton Rouge, LA 70808. E-mail: obrosoig{at}pbrc.edu

Abbreviations: HSC, human Schwann cell; ISO, 1,5-isoquinolinediol; LIS, lisinopril; MAPK, mitogen-activated protein kinase; MNCV, motor nerve conduction velocity; NBF, nutritive blood flow; PARP, poly(ADP-ribose) polymerase; PDN, peripheral diabetic neuropathy; RNAi, RNA interference; SAL, salbutamol; SNCV, sensory nerve conduction velocity; STZ, streptozotocin; TNF-{alpha}, tumor necrosis factor-{alpha}


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