title: DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats.
abstract: 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 < 0.05) by 61% from 20.7 ± 4.2% in the vehicle treated to 8.1 ± 1.6% in the Zebularine treated. Zebularine (100 μg) also reduced infarct volumes dramatically by 55 to 9.4 ± 1.2%. 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.
authors.affiliation: 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 Östergötland, Linköping University, 581 85, Linköping, Sweden, hua.dock@liu.se.
authors.forename: Hua
authors.initials: H
authors.lastname: Dock
authors.forename: Annette
authors.initials: A
authors.lastname: Theodorsson
authors.forename: Elvar
authors.initials: E
authors.lastname: Theodorsson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D003562:Cytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion
chemical_list: D004791:Enzyme Inhibitors; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside
references.citation: Stroke. 1993 Dec;24(12):2121-7
references.pmid: 8248999
references.citation: Mol Pharmacol. 2006 Dec;70(6):1876-84
references.pmid: 16946032
references.citation: Sci Rep. 2013 Nov 01;3:3111
references.pmid: 24177749
references.citation: Oncogene. 2007 Jan 4;26(1):77-90
references.pmid: 16799634
references.citation: Circulation. 2009 Jan 27;119(3):e21-181
references.pmid: 19075105
references.citation: Curr Top Microbiol Immunol. 2000;249:135-64
references.pmid: 10802943
references.citation: Mol Pharmacol. 1983 Jul;24(1):109-14
references.pmid: 6191192
references.citation: PLoS One. 2010 Aug 24;5(8):e12388
references.pmid: 20808780
references.citation: Cancer Chemother Pharmacol. 1992;30(1):7-11
references.pmid: 1375134
references.citation: Cell Death Differ. 2006 Apr;13(4):539-50
references.pmid: 16167067
references.citation: J Med Chem. 1991 Nov;34(11):3280-4
references.pmid: 1956046
references.citation: Nat Genet. 1998 Jun;19(2):187-91
references.pmid: 9620779
references.citation: Stroke Res Treat. 2013;2013:473416
references.pmid: 23365789
references.citation: J Med Chem. 1986 Aug;29(8):1374-80
references.pmid: 3735306
references.citation: J Natl Cancer Inst. 2005 Oct 19;97(20):1498-506
references.pmid: 16234563
references.citation: Brain Res. 2013 Jun 13;1514:83-90
references.pmid: 23340160
references.citation: Cancer Res. 1998 Mar 15;58(6):1245-52
references.pmid: 9515812
references.citation: Neuropeptides. 2011 Feb;45(1):17-23
references.pmid: 20974494
references.citation: Genes Dev. 2007 May 15;21(10):1169-78
references.pmid: 17470536
references.citation: Cell. 1983 May;33(1):9-10
references.pmid: 6205762
references.citation: Bioessays. 1995 May;17(5):423-30
references.pmid: 7786288
references.citation: J Med Chem. 1978 Feb;21(2):204-8
references.pmid: 74412
references.citation: Nature. 1998 May 28;393(6683):386-9
references.pmid: 9620804
references.citation: Neurosci Lett. 2008 Jul 25;440(1):49-53
references.pmid: 18539393
references.citation: Nature. 1998 Aug 27;394(6696):842
references.pmid: 9732866
references.citation: J Neurosci. 2000 May 1;20(9):3175-81
references.pmid: 10777781
references.citation: Neurobiol Dis. 2013 Jan;49:177-89
references.pmid: 22971966