New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-α

Viktor R. Drel, Sergey Lupachyk, Hanna Shevalye, Igor Vareniuk, Weizheng Xu, Jie Zhang, Nicholas A. Delamere, Mohammad Shahidullah, Barbara Slusher, Irina G. Obrosova

Producción científica: Articlerevisión exhaustiva

77 Citas (Scopus)

Resumen

This study evaluated poly(ADP-ribose) polymerase (PARP) inhibition as anewtherapeutic approach for peripheral diabetic neuropathy using clinically relevant animal model and endpoints, and nitrotyrosine (NT), TNF-α, and nitrite/nitrate as potential biomarkers of the disease. Control and streptozotocin-diabetic rats were maintained with or without treatment with orally active PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2- diaza-benzo[de]anthracen-3-one (GPI-15,427), 30 mg kg-1 d -1, for 10 wk after first 2 wk without treatment. Therapeutic efficacy was evaluated by poly(ADP-ribosyl)ated protein expression (Western blot analysis), motor and sensory nerve conduction velocities, and tibial nerve morphometry. Sciatic nerve and spinal cord NT, TNF-α, and nitrite/nitrate concentrations were measured by ELISA. NT localization in peripheral nervous system was evaluated by double-label fluorescent immunohistochemistry. A PARP inhibitor treatment counteracted diabetes-induced motor and sensory nerve conduction slowing, axonal atrophy of large myelinated fibers, and increase in sciatic nerve and spinal cord NT and TNF-α concentrations. Sciatic nerve NT and TNF-α concentrations inversely correlated with motor and sensory nerve conduction velocities and myelin thickness, whereas nitrite/nitrate concentrations were indistinguishable between control and diabetic groups. NT accumulation was identified in endothelial and Schwann cells of the peripheral nerve, neurons, astrocytes, and oligodendrocytes of the spinal cord, and neurons and glial cells of the dorsal root ganglia. The findings identify PARP as a compelling drug target for prevention and treatment of both functional and structural manifestations of peripheral diabetic neuropathy and provide rationale for detailed evaluation of NT and TNF-α as potential biomarkers of its presence, severity, and progression.

Idioma originalEnglish (US)
Páginas (desde-hasta)2547-2555
Número de páginas9
PublicaciónEndocrinology
Volumen151
N.º6
DOI
EstadoPublished - jun 2010
Publicado de forma externa

ASJC Scopus subject areas

  • Endocrinology

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