Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mecha-nisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP/) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP/) diabetic or galac-tose-fed mice. Two structurally unrelated PARP inhibi-tors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induce