Li W, Luo Y, Zhang F, Signore AP, Gobbel GT, Simon RP, Chen JIschemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. J Cereb Blood Flow Metab 26:181-198

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 03/2006; 26(2):181-98. DOI: 10.1038/sj.jcbfm.9600180
Source: PubMed


The development of ischemic tolerance in the brain, whereby a brief period of sublethal 'preconditioning' ischemia attenuates injury from subsequent severe ischemia, may involve the activation of multiple intracellular signaling events that promote neuronal survival. In this study, the potential role of inducible DNA base-excision repair (BER), an endogenous adaptive response that prevents the detrimental effect of oxidative DNA damage, has been studied in the rat model of ischemic tolerance produced by three episodes of ischemic preconditioning (IP). This paradigm of IP, when applied 2 and 5 days before 2-h middle cerebral artery occlusion (MCAO), significantly decreased infarct volume in the frontal-parietal cortex 72 h later. Correlated with this protective effect, IP markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA strand breaks, after 2-h MCAO. Consequently, harmful DNA damage-responsive events, including NAD depletion and p53 activation, were reduced during postischemic reperfusion in preconditioned brains. The mechanism underlying the decreased DNA damage in preconditioned brain was then investigated by measuring BER activities in nuclear extracts. Beta-polymerase-mediated BER activity was markedly increased after IP, and this activation occurred before (24 h) and during the course of ischemic tolerance (48 to 72 h). In similar patterns, the activities for AP site and 8-oxodG incisions were also upregulated after IP. The upregulation of BER activities after IP was likely because of increased expression of repair enzymes beta-polymerase, AP endonuclease, and OGG1. These results suggest that the activation of the BER pathway may contribute to IP-induced neuroprotection by enhancing the repair of endogenous oxidative DNA damage after ischemic injury.

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Available from: Glenn Gobbel, May 21, 2015
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    • "Apurinic/apyrimidinic endonuclease-1 (APE1) is one of the key enzymes in the base excision repair (BER) pathway; its function is to cleave the apurinic/apyrimidinic sites (Parsons et al., 2004; Srivastava et al., 1998). Our previous studies demonstrate that APE1 contributes to inducible DNA repair after ischemic preconditioning (Li et al., 2005) and to the neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) (Stetler et al., 2010). We also show that NAD + treatment protects cultured neurons against ischemic injury via enhancing the BER pathway (Wang et al., 2008). "
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    • "With regards to brain damage from a stroke, our findings suggest that neurons that are better able to repair oxidative DNA lesions have an increased chance of survival. This conclusion is consistent with the results of previous studies of BER activity in models of ischemic stroke (Li et al, 2006). Moreover, mice deficient in uracil-DNA glycosylase, another DNA glycosylase that initiates BER of uracil lesions, also exhibit increased neuronal vulnerability to experimental stroke (Endres et al, 2004). "
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