TY - JOUR
T1 - PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy
AU - Obrosova, Irina G.
AU - Xu, Weizheng
AU - Lyzogubov, Valeriy V.
AU - Ilnytska, Olga
AU - Mashtalir, Nazar
AU - Vareniuk, Igor
AU - Pavlov, Ivan A.
AU - Zhang, Jie
AU - Slusher, Barbara
AU - Drel, Viktor R.
N1 - Funding Information:
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.
PY - 2008/3/15
Y1 - 2008/3/15
N2 - 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 ∼ 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.
AB - 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 ∼ 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.
KW - Free radicals
KW - Intraepidermal nerve fiber loss
KW - Mechanical hyperalgesia
KW - Mechanical hypoalgesia
KW - Neuropathic pain
KW - Oxidative-nitrosative stress
KW - Poly(ADP-ribose) polymerase
KW - Tactile allodynia
KW - Thermal hypoalgesia
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U2 - 10.1016/j.freeradbiomed.2007.09.013
DO - 10.1016/j.freeradbiomed.2007.09.013
M3 - Article
C2 - 17976390
AN - SCOPUS:39849088155
SN - 0891-5849
VL - 44
SP - 972
EP - 981
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 6
ER -