5 enhancing the expression of the dna repair/redox enzyme, ape1/ref-1, reduces neurotoxicity induced by ionizing radiation: implications for decreasing pediatric neurocognitive dysfunction.

ABSTRACT Neurotoxicity which includes both neurocognitive dysfunction commonly called “chemobrain” and peripheral neuropathy, occurs frequently in pediatric patients who receive ionizing

radiation (IR) for the treatment of cancer. Despite the prevalence of these side effects, little work has been done to elucidate the mechanisms of or interventions to prevent neurotoxicity.

Apurinic/apyrimidinic endonuclease/redox effector factor (Ape1) repairs AP sites in DNA secondary to oxidative damage and regulates the redox state of transcription factors. Because IR

produces reactive oxygen species and DNA damage, we examined whether overexpressing Ape1 in primary neuronal cultures reduces toxicity after IR. To decrease the expression of Ape1, rat

hippocampal or sensory neuronal cultures were exposed to small interfering RNA to Ape1 (Ape1siRNA) or to scramble siRNA (SCsiRNA) as a control. To overexpress Ape1, cells treated with siRNA

were subsequently exposed to adenoviral constructs containing Ape1 or to a vector control. Cultured cells in the absence or presence of altered expression of Ape1 were then exposed to IR and

three endpoints examined, cell viability, DNA double strand breaks, and neurotransmitter release. Exposing neurons to increasing amounts of IR resulted in a dose–dependent increase in cell

death 24 hours after the treatment. Reducing Ape1 expression with Ape1siRNA by ∼ 85-95% significantly augmented IR-induced cell death compared to cultures treated with SCsiRNA. In a similar

manner, reductions in Ape1 in neuronal cultures doubled the IR-induced phosphorylation of histone 2A.X, indicating an increase in DNA double-strand breaks. Overexpressing Ape1 in neuronal

cultures treated with SCsiRNA or Ape1siRNA resulted in a significant increase in cell viability and a 4-6 fold reduction in H2A.X phosphorylation after exposure to IR. IR significantly

reduced the stimulated release if calcitonin gene-related peptide (CGRP) from sensory neurons from 10.2 ± 0.5 5 of the total content of CGRP to 7.5 0.7%. This reduction in release was

augmented by reducing Ape1 expression by 85% and revered by overexpressing Ape1. These data demonstrate that Ape1 plays an important role in minimizing neurotoxicity secondary to oxidative

stress and modulation of Ape1's functions could lead to protection of neuronal cell damage and killing during IR treatments. ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Dept of Pharmacol and Toxicol, Indianapolis, 46202, IN, USA M R Vasko & C Guo * Wells Ctr Pediatric Res, Indiana University School of Medicine, Indianapolis, 46202, IN, USA C Guo, Y L

Jiang & M R Kelley Authors * M R Vasko View author publications You can also search for this author inPubMed Google Scholar * C Guo View author publications You can also search for this

author inPubMed Google Scholar * Y L Jiang View author publications You can also search for this author inPubMed Google Scholar * M R Kelley View author publications You can also search for

this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Vasko, M., Guo, C., Jiang, Y. _et al._ 5 Enhancing the Expression of

the Dna Repair/Redox Enzyme, Ape1/Ref-1, Reduces Neurotoxicity Induced by Ionizing Radiation: Implications for Decreasing Pediatric Neurocognitive Dysfunction.. _Pediatr Res_ 60, 491 (2006).

https://doi.org/10.1203/00006450-200610000-00027 Download citation * Issue Date: 01 October 2006 * DOI: https://doi.org/10.1203/00006450-200610000-00027 SHARE THIS ARTICLE Anyone you share

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