PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function.

Abstract

This study evaluated the role of poly(ADP-ribose) polymerase (PARP) in systemic oxidative stress and 4-hydoxynonenal adduct accumulation in diabetic peripheral neuropathy. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor, 1,5-isoquinolinediol, 3 mg kg(-1) day(-1), for 10 weeks after an initial 2 weeks. Treatment efficacy was evaluated by poly(ADP-ribosyl)ated protein content in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons and nonneuronal cells (fluorescence immunohistochemistry), as well as by indices of peripheral nerve function. Diabetic rats displayed increased urinary isoprostane and 8-hydroxy-2'-deoxyguanosine excretion (ELISA) and 4-hydroxynonenal adduct accumulation 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 (double-label fluorescence immunohistochemistry), as well as motor and sensory nerve conduction velocity deficits, thermal hypoalgesia, and tactile allodynia. PARP inhibition counteracted diabetes-induced systemic oxidative stress and 4-hydroxynonenal adduct accumulation in peripheral nerve and spinal cord (Western blot analysis) and dorsal root ganglion neurons (perikarya, fluorescence immunohistochemistry), which correlated with improvement of large and small nerve fiber function. The findings reveal the important role of PARP activation in systemic oxidative stress and 4-hydroxynonenal adduct accumulation in diabetic peripheral neuropathy.

• Authors: Sergey Lupachyk, Hanna Shevalye, Yury Maksimchyk, Viktor R Drel, Irina G Obrosova
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 50 Issue 10 Pg. 1400-9 (May 15 2011) ISSN: 1873-4596 [Electronic] United States
• PMID: 21300148 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011. Published by Elsevier Inc.

Chemical References

• Aldehydes
• Isoquinolines
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinolines
• 1,5-dihydroxyisoquinoline
• Poly(ADP-ribose) Polymerases
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (metabolism)
• Animals
• Diabetes Mellitus, Experimental (metabolism)
• Isoquinolines
• Male
• Nerve Tissue (chemistry, drug effects, metabolism)
• Oxidative Stress (drug effects)
• Peripheral Nerves (drug effects, metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Quinolines (pharmacology)
• Rats
• Rats, Wistar