PARP INHIBITION OR GENE DEFICIENCY COUNTERACT INTRAEPIDERMAL NERVE FIBER LOSS AND NEUROPATHIC PAIN IN ADVANCED DIABETIC NEUROPATHY

• Published in: Free radical biology & medicine 2007-10, Vol.44 (6), p.972-981
• Main Authors: Obrosova, Irina G., Xu, Weizheng, Lyzogubov, Valeriy V., Ilnytska, Olga, Mashtalir, Nazar, Vareniuk, Igor, Pavlov, Ivan A., Zhang, Jie, Slusher, Barbara, Drel, Viktor R.
• Format: Article
• Language: English
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2007.09.013

Evidence for important role of poly(ADP-ribose) polymerase (PARP) activation in diabetic complications is emerging. This study evaluated the role for PARP in rat and mouse models of advanced diabetic neuropathy. The orally active PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one(GPI-15427, formulated as mesilate salt, 30 mg kg −1 d −1 in the drinking water, for 10 weeks after 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, the most important, 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−/− preserved 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 the rationale for development of potent and low toxic PARP inhibitors and PARP inhibitor-containing combination therapies.