Editors' ChoicePeripheral Diabetic Neuropathy

The Latest PARP Sensation

See allHide authors and affiliations

Science Translational Medicine  02 Jun 2010:
Vol. 2, Issue 34, pp. 34ec87
DOI: 10.1126/scitranslmed.3001314

Diabetic patients must control their blood glucose for a variety of reasons, including to prevent life-altering complications such as peripheral diabetic neuropathy (PDN)—damage to peripheral nerves that leads to impaired sensation and movement. Peripheral nerves carry impulses from the central nervous system to other regions of the body, such as fingers and feet. Despite extensive investigations into the root causes of PDN, there are currently no treatments that function by modulating the disease mechanism. Now, Drel et al. describe data that assess a new mechanistic approach to this debilitating disease.

Poly(ADP-ribose) polymerase-1 (PARP), which catalyzes the formation of adenosine 5'-diphosphate (ADP) ribose polymers and transfers them to target proteins, has been proposed as a target for PDN drug development. Several factors support the investigation of PARP as a target for diabetic neuropathy, but most notable is that PARP selectively resides in the peripheral nerves, spinal cord, and dorsal root ganglia of animal models of diabetes (types 1 and 2) and prediabetic neuropathy, relative to control animals. In a prior study, Drel et al. used this information to illustrate that activation of PARP is responsible for diabetes-related impairment in peripheral nerve conduction and blood flow, neuropathic pain, impotence, and gastroparesis (a condition that hinders the ability of the stomach to empty). In their recent paper, the authors use these insights to explore PARP inihibition as a therapy for PDN and in the identification of disease-specific biomarkers.

Drel et al. used a streptozotocin-induced rat model of diabetes that mimics both the structural and functional changes associated with human PDN to study the effects of a known PARP inhibitor on several physiological parameters altered by PDN: diabetes-associated motor and sensory nerve conduction; axonal atrophy of large myelinated nerve fibers; nitrotyrosine levels; and production of tumor necrosis factor–α (TNF-α), which is a potent proinflammatory cytokine. They compared these parameters in untreated and PARP inhibitor–treated diabetic rats and control nondiabetic rats. The authors found that poly(ADP-ribosyl)ated proteins were increased in the peripheral nerves and spinal cords of diabetic rats as compared with those of the control rats, as expected. However, when they examined the PARP inhibitor–treated diabetic rats they discovered that the elevation in poly(ADP-ribosyl)ated proteins was essentially eliminated. Also, in diabetic rats, nerve conduction velocities were impaired, axonal atrophy was evident, and nitrotyrosine and TNF-α amounts were increased relative to control rats. All of these parameters were improved by administration of the PARP inhibitor.

This study highlights the benefit of having a robust rat disease model that mimics the human condition in the elucidation of potential drug action. Furthermore, this model points the way for more studies on the utility of nitrotyrosine and TNF-α as biomarkers for PDN monitoring.

V. R. Drel et al., New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-α. Endocrinology 151, 2547–2555 (2010). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article