Article

Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway.

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.4). 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.

0 Bookmarks
 · 
61 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.
    Nature Neuroscience 04/2014; · 15.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose. Treatment with light in the far-red to near-infrared region of the spectrum (photobiomodulation [PBM]) has beneficial effects in tissue injury. We investigated the therapeutic efficacy of 670 nm PBM in rodent and cultured cell models of diabetic retinopathy. Methods. Studies were conducted in streptozotocin-induced diabetic rats and in cultured retinal cells. Diabetes-induced retinal degeneration was assessed functionally, biochemically and histologically in vivo and in vitro. Results. We observed beneficial effects of PBM on the neural and vascular elements of retina. Daily 670 nm PBM treatment (6 J/cm(2)) resulted in significant inhibition in the diabetes-induced death of retinal ganglion cells, as well as, a 50% improvement of the ERG amplitude (photopic b wave responses) (both p<0.01). To explore the mechanism for these beneficial effects, we examined physiologic and molecular changes related cell survival, oxidative stress and inflammation. PBM did not alter cytochrome oxidase activity in the retina or in cultured retinal cells. PBM inhibited diabetes-induced superoxide production and preserved MnSOD expression in vivo. Diabetes significantly increased both leukostasis and expression of ICAM-1, and PBM essentially prevented both of these abnormalities. In cultured retinal cells, 30mM glucose exposure increased superoxide production, inflammatory biomarker expression and cell death. PBM inhibited all of these abnormalities. Conclusions. PBM ameliorated diabetic retinopathy in vivo and reduced oxidative stress and cell death in vitro. PBM has been documented to have minimal risk. PBM is noninvasive, inexpensive, and easy to administer. We conclude that PBM is a simple adjunct therapy to attenuate the development of diabetic retinopathy.
    Investigative ophthalmology & visual science 04/2013; · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral ischemic preconditioning (IPC), which refers to a transient and noninjurious ischemia is able to induce tolerance against the subsequent lethal ischemia, including ischemic stroke. We have previously reported that bone morphogenic protein-7 (BMP-7) contributes to the neuroprotective effects of IPC-induced ischemic tolerance, and thus ameliorates the following ischemia/reperfusion (I/R) injury in rats. Consequently, in the present study, we continued to explore the underlying regulatory mechanisms involved in BMP-7-mediated cerebral IPC in the rat model of ischemic tolerance. Male Wistar rats were preconditioned by 15-min middle cerebral artery occlusion (MCAO). After 2-day reperfusion, these animals were subjected to prolonged MCAO for 2 h. Our results showed that the phosphorylated p38 mitogen-activated protein kinase (MAPK) paralleling to BMP-7 was up-regulated by IPC in rat brain. Inactivation of p38 MAPK by pretreatment of SB203580, a p38 MAPK-specific suppressor, weakened the protective effect of IPC on CA1 neurons. Moreover, the enhanced phosphorylation of p38 MAPK induced by IPC was attenuated when the endogenous BMP-7 was inhibited by BMP-7 antagonist noggin. Besides, blockade of p38 MAPK signal transduction pathway via SB203580 abrogated the protective effects of exogenous BMP-7 against cerebral infraction. These present findings suggest that BMP-7 contributes to cerebral IPC-induced ischemic tolerance via activating p38 MAPK signaling pathway.
    Inflammation 02/2014; · 2.46 Impact Factor

Full-text

View
0 Downloads
Available from