PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy.
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.
Obrosova
Irina G
IG
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA. obrosoig@pbrc.edu
Xu
Weizheng
W
Lyzogubov
Valeriy V
VV
Ilnytska
Olga
O
Mashtalir
Nazar
N
Vareniuk
Igor
I
Pavlov
Ivan A
IA
Zhang
Jie
J
Slusher
Barbara
B
Drel
Viktor R
VR
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000209:etiology / Q000517:prevention & control*; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control*; D009930:Organic Chemicals / Q000627:therapeutic use; D010525:Peripheral Nerves / Q000187:drug effects* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000294:innervation
D004791:Enzyme Inhibitors; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C502278:GPI 15427; D011065:Poly(ADP-ribose) Polymerases