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

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 approximately 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.

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

“…Note, that a significant (p<0.05) increase in intraepidermal nerve fiber density was achieved in STZ-diabetic mice treated with 5 mg kg −1 day −1 and 10 mg kg −1 day −1 of another peroxynitrite decomposition catalyst, Fe(III) tetramesitylporphyrin octasulfonate . Furthermore, whereas PARP+/+ mice with 10-week duration of STZ-diabetes displayed ~53% intraepidermal nerve fiber loss, diabetic PARP−/− preserved completely normal intraepidermal nerve fiber density (Obrosova et al, 2007a). The latter supports the important role of nitrosative stress in small sensory nerve fiber degeneration associated with PDN, because peroxynitrite provides a major contribution to PARP activation in tissues-sites for diabetic complications including PNS Pacher et al, 2005;Szabo et al, 2002a).…”

“…As indicated above, neurotrophic factors as well as PARP inhibitors prevented thermal hypoalgesia in STZ-diabetic rats (Calcutt et al, 2000Obrosova et al, 2007a). PARP inhibition counteracted thermal hypoalgesia, mechanical hyperalgesia, and tactile allodynia in rats with 12-week duration of STZ-diabetes (Obrosova et al, 2007a).…”

“…Taurine prevented thermal hyperalgesia in ZDF rats (Li et al, 2006). Insulin therapy resulting in achievement of protracted normoglycemia (Calcutt, 2002(Calcutt, , 2004, ARIs , Schwann cell-derived ciliary neurotrophic factor (CNTF) , the neurotrophic peptide deriving from prosaposin, TX14(A), (Calcutt et al, 2000), and a sonic hedgehog-IgG fusion protein (Calcutt et al, 2003), as well as PARP inhibitors (Obrosova et al, 2007a) prevented or alleviated thermal hypoalgesia in STZ-diabetic rats with longer duration of diabetes. Thus, pharmacological studies in diabetic animal models revealed importance of hyperglycemia, increased aldose reductase and protein kinase C activities, impaired neurotrophic support, as well as oxidative stress and PARP activation, in thermal hyper-and hypoalgesia associated with PDN.…”

“…The findings of the present study suggest that RNS contribute to the development of diabetes-associated mechanical hypoalgesia. This effect could at least partially be due to resultant PARP activation as STZdiabetic PARP-deficient mice did not develop mechanical hypoalgesia that was clearly manifest in diabetic wild-type mice (Obrosova et al, 2007a).…”

“…Accumulation of nitrotyrosine [NT, a footprint of peroxynitrite-and other reactive nitrogen species (RNS)-induced protein nitration] has been documented in vascular endothelium (Pacher et al, 2005;Szabo et al, 2002b), myocardium (Pacher et al, 2005), retina (Cheung et al, 2005;Obrosova et al, 2005c), and kidneys (Drel et al, 2006b) of streptozotocin-diabetic rats and mice as well as cutaneous microvascular endothelium (Szabo et al, 2002b), myocardium (Frustaci et al, 2000), and kidneys (Thuraisingham et al, 2000) of human subjects with diabetes. Increased NT immunoreactivity has also been demonstrated in peripheral nervous system i.e., peripheral nerve, spinal cord and dorsal root ganglion (DRG) neurons, of STZ-diabetic rats (Cheng and Zochodne, 2003;Obrosova et al, 2005a) and STZ-diabetic (Ho et al, 2006;Obrosova et al, 2005b), ob/ob (Drel et al, 2006a), and high-fat diet fed mice (Obrosova et al, 2007b), and epineurial vessels of STZ-diabetic, ZDF diabetic fatty, and Zucker fatty rats (Coppey et al, 2001; Obrosova et al, 2005a,b;Oltman et al, 2005). Enhanced nitrosative stress has been reported in human subjects with peripheral diabetic neuropathy (Hoeldtke, 2003).…”