DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats

详细信息    查看全文

• 作者：Hua Dock ; Annette Theodorsson ; Elvar Theodorsson
• 关键词：Zebularine ; DNA methylation inhibitor ; Ischemic stroke ; Neuroprotection
• 刊名：Translational Stroke Research
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：6
• 期：4
• 页码：296-300
• 全文大小：312 KB
• 参考文献：1.Liu R, Yang SH. Window of opportunity: estrogen as a treatment for ischemic stroke. Brain Res. 2013;1514:83-0.PubMed Central PubMed View Article
  2.Writing Group Members, Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, et al. Heart disease and stroke statistics-009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):e21-81.View Article
  3.WHO Stroke, Cerebrovascular accident. World Health Organization. 2011.Available: http://?www.?who.?int/?topics/?cerebrovascular accident/?en/-/span> .
  4.Wainer D. Strokes killing younger people as unhealthy habits rise. 2013. Available: http://?www.?bloomberg.?com/?news/-013-10-23/?strokes-killing-younger-people-as-unhealthy-habits-rise.?html .
  5.Endre M, Meisel A, Biniszkiewicz D, Namura S, Prass K, Ruscher K, et al. DNA methyltransferase contributes to delayed ischemic brain injury. J Neurosci. 2000;20(9):3175-1.
  6.Brown SE, Weaver IG, Meaney MJ, Szyf M. Regional-specific global cytosine methylation and DNA methyltransferase expression in the adult rat hippocampus. Neurosci Lett. 2008;440(1):49-3.PubMed View Article
  7.Bouchard J, Momparler RL. Incorporation of 5-Aza-2 deoxycytidine-5-triphosphate into DNA. Interactions with mammalian DNApolymerase α and DNA methylase. Mol Pharmacol. 1983;24(1):109-4.PubMed
  8.Santi DV, Garrett CE, Barr PJ. On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell. 1983;33(1):9-0.PubMed View Article
  9.Kogure K, Kato H. Altered gene expression in cerebral ischemia. Stroke. 1993;24(10):2121-.PubMed View Article
  10.Lubbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol. 2000;249:135-4.PubMed
  11.Kim CH, Marquez VE, Mao DT, Haines DR, McCormack JJ. Synthesis of pyrimidin-2-one nucleosides as acid-stable inhibitors of cytidine deaminase. J Med Chem. 1986;29(8):1374-0.PubMed View Article
  12.Laliberte J, Marquez VE, Momparler RL. Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2-deoxycytidine by human cytidine deaminase. Cancer Chemother Pharmacol. 1992;30(1):7-1.PubMed View Article
  13.Gonzalgo ML, Hayashida T, Bender CM, Pao MM, Tsai YC, Gonzales FA, et al. The role of DNA methylation in expression of the p19/p16 locusin human bladder cancer cell lines. Cancer Res. 1998;58(6):1245-2.PubMed
  14.Driscoll JS, Marquez VE, Plowman J, Liu PS, Kelley JA, Barchi Jr JJ. Antitumor properties of 2(1H)-pyrimidinone riboside (zebularine) and its fluorinated analogues. J Med Chem. 1991;34(11):3280-.PubMed View Article
  15.Beisler JA. Isolation, characterization, and properties of a liable hydrolysis product of the antitumor nucleoside, 5-azacytidine. J Med Chem. 1978;21(2):204-.PubMed View Article
  16.Holm L, Theodorsson E, H?kfelt T, Theodorsson A. Effects of intracerebroventricular galanin or a galanin receptor 2/3 agonist on the lesion induced by transient occlusion of the middle cerebral artery in female rats. Neuropeptides. 2011;45(1):17-3.PubMed View Article
  17.Lyko F, Brown B. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst. 2005;97(20):1498-06.PubMed View Article
  18.Str?m JO, Ingberg E, Theodorsson E, Theodorsson A. Effects of high and low 17?-estradiol doses on focal cerebral ischemia: negative results. Sci Rep. 2013;3:3111. doi:10.-038/?srep03111 .PubMed View Article
  19.Champion C, Guianvarch D, Senamaud-Beaufort C, Jurkowska RZ, Jeltsch A, Ponger L, et al. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One. 2010;5(8):e12388.PubMed Central PubMed View Article
  20.Yoshida M, Horinouchi S, Beppu T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioassays. 1995;17(5):423-0.View Article
  21.Eden S, Hashimshony T, Keshet I, Cedar H, Thorne AW. DNA methylation models histone acetylation. Nature. 1998;394(6696):842.PubMed View Article
  22.Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19(2):187-1.PubMed View Article
  23.Nan X, Ng HH, Johnson CA, Laherty CD, Turner BT, Eisenmann RN, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393(6683):386-.PubMed View Article
  24.Smallwood A, Esteve PO, Pradhan S, Carey M. Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev. 2007;21(10):1169-8.PubMed Central PubMed View Article
  25.Faraco G, Pancani T, Formentini L, Mascaqni P, Fossati G, Leoni F, et al. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic
• 作者单位：Hua Dock (1)
  Annette Theodorsson (2)
  Elvar Theodorsson (1)
  
  1. Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Department of Clinical Chemistry, Center for Diagnostics, County Council of ?sterg?tland, Link?ping University, 581 85, Link?ping, Sweden
  2. Division of Neuroscience, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Department of Neurosurgery, Anaesthetics, Operations and Specialty Surgery Center, County Council of ?sterg?tland, Link?ping University, Link?ping, Sweden
  
• 刊物主题：Neurosciences; Neurology; Cardiology; Neurosurgery; Vascular Surgery;
• 出版者：Springer US
• ISSN：1868-601X

文摘

5-Aza-deoxycytidine (5-aza-dC) confers neuroprotection in ischemic mice by inhibiting DNA methylation. Zebularine is another DNA methylation inhibitor, less toxic and more stable in aqueous solutions and, therefore more biologically suitable. We investigated Zebularine’s effects on brain ischemia in a rat middle cerebral artery occlusion (MCAo) model in order to elucidate its therapeutic potential. Male Wistar wild-type (WT) rats were randomly allocated to three treatment groups, vehicle, Zebularine 100?μg, and Zebularine 500?μg. Saline (10?μL) or Zebularine (10?μL) was administered intracerebroventricularly 20?min before 45-min occlusion of the middle cerebral artery. Reperfusion was allowed after 45-min occlusion, and the rats were sacrificed at 24-h reperfusion. The brains were removed, sliced, and stained with 2?% 2,3,5-triphenyltetrazolium chloride (TTC) before measuring infarct size. Zebularine (500?μg) reduced infarct volumes significantly (p-lt;-.05) by 61?% from 20.7?±-.2?% in the vehicle treated to 8.1?±-.6?% in the Zebularine treated. Zebularine (100?μg) also reduced infarct volumes dramatically by 55 to 9.4?±-.2?%. The mechanisms behind this neuroprotection is not yet known, but the results agree with previous studies and support the notion that Zebularine-induced inhibition of DNA methyltransferase ameliorates ischemic brain injury in rats.