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

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 03/2006; 26(2):181-98. DOI: 10.1038/sj.jcbfm.9600180
Source: PubMed

ABSTRACT 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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    ABSTRACT: Silent information regulator two proteins (sirtuins or SIRTs) are a group of histone deacetylases whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD(+)). They suppress genome-wide transcription, yet upregulate a select set of proteins related to energy metabolism and pro-survival mechanisms, and therefore play a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of sirtuins has been reported for both acute and chronic neurological diseases. The focus of this review is to summarize the latest progress regarding the protective effects of sirtuins, with a focus on SIRT1. We first introduce the distribution of sirtuins in the brain and how their expression and activity are regulated. We then highlight their protective effects against common neurological disorders, such as cerebral ischemia, axonal injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Finally, we analyze the mechanisms underlying sirtuin-mediated neuroprotection, centering on their non-histone substrates such as DNA repair enzymes, protein kinases, transcription factors, and coactivators. Collectively, the information compiled here will serve as a comprehensive reference for the actions of sirtuins in the nervous system to date, and will hopefully help to design further experimental research and expand sirtuins as therapeutic targets in the future.
    Progress in Neurobiology 09/2011; 95(3):373-95. DOI:10.1016/j.pneurobio.2011.09.001 · 9.99 Impact Factor
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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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    ABSTRACT: 7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1(-/-) mice compared with OGG1(+/+) mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2011; 31(2):680-92. DOI:10.1038/jcbfm.2010.147 · 5.41 Impact Factor
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    • "There are some reports of using 3-20 minutes of focal ischemia, but almost all of these short durations of ischemia are used for the induction of " preconditioning " or " ischemia-induced tolerance " (Chen et al., 1996; Li et al., 2006; Currie et al., 2000; Puisieux et al., 2004; Shimizu et al., 2001; Dhodda et al., 2004; Naylor et al., 2005). Focal ischemia as short as 3 minutes produced preconditioning (Puisieux et al., 2004), with three 10 minute episodes of preconditioning appearing to produce the best protection against focal infarction (Chen et al., 1996; Li et al., 2006). "
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    Brain Research 09/2008; 1234:183-97. DOI:10.1016/j.brainres.2008.07.094 · 2.84 Impact Factor
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