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Abstract

Click to add/remove this article to your list of 'My Favorites' PARP Inhibition or Gene Deficiency Counteract Intraepidermal Nerve Fiber Loss and Neuropathic Pain Associated with Type 1 Diabetes

Year: 2007

Abstract Number: 0001-OR

Authors: IRINA G. OBROSOVA, VALERIY LYZOGUBOV, OLGA ILNYTSKA, NAZAR MASHTALIR, IGOR VARENIUK, IVAN PAVLOV, WEIZHENG XU, JIE ZHANG, VIKTOR R. DREL, Baton Rouge, LA, Baltimore, MD

Results: Evidence for important role of poly(ADP-ribose) polymerase (PARP) activation in diabetic complications is emerging. This work was aimed at evaluating the role for PARP in intraepidermal nerve fiber loss and diabetic neuropathic pain in rat and mouse models of STZ-diabetes. The experiments have been performed in 1) rats with 12-wk duration of diabetes treated with the orally active PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427, MGI Pharma, Baltimore, 30 mg kg-1d-1 in the drinking water, for 10 weeks after first 2 weeks without treatment); and 2) diabetic PARP+/+ and PARP-/- mice. Body weights were similarly reduced and blood glucose concentrations similarly increased in untreated and GPI-15427-treated diabetic rats compared with controls. Diabetic rats displayed an increase in 4-hydroxynonenal adduct (marker of lipid peroxidation), nitrotyrosine (marker of peroxynitrite injury) and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and DRG neurons. Functional and morphometric studies revealed the presence of mechanical hyperalgesia, tactile allodynia, exaggerated flinching behavior in the second phase of the formalin pain test, as well as ∼ 47% loss of intraepidermal nerve fibers, consistent with thermal hypoalgesia. GPI-15427 at least partially prevented diabetes-induced oxidative-nitrosative stress and PARP activation in peripheral nerve, spinal cord and DRG neurons, as well as mechanical hyperalgesia, tactile allodynia, exaggerated response to formalin, and, the most important, intraepidermal nerve fiber degeneration. These findings are consistent with less severe small sensory fiber neuropathy in diabetic PARP-/- mice compared to wild-type mice with STZ-diabetes of similar duration (10 weeks) and severity. Furthermore, whereas diabetic PARP+/+ mice displayed ∼ 53% intraepidermal nerve fiber loss, diabetic PARP-/- preserved completely normal intraepidermal nerve fiber density. In conclusion, PARP activation is an important contributor to intraepidermal nerve fiber degeneration and neuropathic pain associated with Type 1 diabetes.The results support the rationale for development of potent and low toxic PARP inhibitors and PARP inhibitor-containing combination therapies. Support: JDRF 1-2005-223