title: Orally administrated ascorbic acid suppresses neuronal damage and modifies expression of SVCT2 and GLUT1 in the brain of diabetic rats with cerebral ischemia-reperfusion.
abstract: Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.
authors.affiliation: Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. n-iwata@josai.ac.jp.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. okazaki@josai.ac.jp.
authors.forename: Mari
authors.initials: M
authors.lastname: Okazaki
authors.affiliation: Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. genbien@josai.ac.jp.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Xuan
authors.affiliation: Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. kamiuchi@josai.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kamiuchi
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. ma-tsu@josai.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsuzaki
authors.affiliation: Laboratory of Immunobiochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan. seitaib@josai.ac.jp.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hibino
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects; D053148:Caspase 3; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D019587:Dietary Supplements; D042783:Endothelial Cells / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051272:Glucose Transporter Type 1; D053583:Interleukin-1beta; C555167:Slc23a2 protein, rat; C495679:Slc2a1 protein, rat; D060347:Sodium-Coupled Vitamin C Transporters; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; C505410:Casp3 protein, rat; D053148:Caspase 3; D001205:Ascorbic Acid
references.citation: Biochim Biophys Acta. 2010 Jan;1802(1):92-9
references.pmid: 19751828
references.citation: J Clin Invest. 1997 Dec 1;100(11):2842-8
references.pmid: 9389750
references.citation: Food Chem Toxicol. 2013 Oct;60:328-40
references.pmid: 23907022
references.citation: J Neurochem. 2009 May;109 Suppl 1:133-8
references.pmid: 19393019
references.citation: Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78
references.pmid: 16490224
references.citation: Behav Brain Res. 2011 Jun 20;220(1):30-41
references.pmid: 21262264
references.citation: Diabetes. 2002 Jun;51(6):1851-8
references.pmid: 12031973
references.citation: Mol Neurobiol. 2010 Jun;41(2-3):242-7
references.pmid: 20195798
references.citation: Neurosurgery. 2006 Aug;59(2):383-8; discussion 383-8
references.pmid: 16883179
references.citation: J Vasc Res. 2004 Jul-Aug;41(4):345-51
references.pmid: 15340249
references.citation: J Neurochem. 2007 Oct;103(2):590-603
references.pmid: 17666052
references.citation: Diabetes. 1991 Apr;40(4):405-12
references.pmid: 2010041
references.citation: Diabetes. 2006 Feb;55(2):349-55
references.pmid: 16443767
references.citation: Exp Brain Res. 2007 Sep;182(1):1-10
references.pmid: 17665180
references.citation: Hypertension. 2004 Nov;44(5):758-63
references.pmid: 15452025
references.citation: Med Clin North Am. 1993 Jan;77(1):95-110
references.pmid: 8419726
references.citation: J Diabetes Complications. 2002 May-Jun;16(3):235-45
references.pmid: 12015194
references.citation: Am J Clin Nutr. 1991 Oct;54(4):712-6
references.pmid: 1897478
references.citation: Brain Res. 2012 Dec 13;1489:113-20
references.pmid: 23078759
references.citation: Neurochem Int. 2005 Apr;46(5):399-407
references.pmid: 15737438
references.citation: Int J Vasc Med. 2012;2012:709695
references.pmid: 22690337
references.citation: Toxicol Lett. 2006 Sep 30;166(1):27-36
references.pmid: 16820274
references.citation: Clin Chim Acta. 1973 Feb 28;44(1):47-52
references.pmid: 4707637
references.citation: PLoS One. 2011 Feb 11;6(2):e17139
references.pmid: 21347255
references.citation: FASEB J. 2007 Dec;21(14):3904-16
references.pmid: 17628015
references.citation: Int J Mol Sci. 2013 Mar 26;14(4):6746-56
references.pmid: 23531536
references.citation: J Neurosci Res. 2006 Apr;83(5):919-28
references.pmid: 16477646
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11720-4
references.pmid: 11573006
references.citation: Toxicol Lett. 1996 Dec 31;89(3):249-56
references.pmid: 9001594
references.citation: Endocrinology. 2013 Nov;154(11):4068-77
references.pmid: 24008345
references.citation: Brain Dev. 2009 Apr;31(4):307-17
references.pmid: 18682317
references.citation: Cell Mol Neurobiol. 2009 Feb;29(1):133-40
references.pmid: 18758938
references.citation: Atherosclerosis. 2009 Feb;202(2):321-9
references.pmid: 18640680
references.citation: Nephrol Dial Transplant. 2011 Apr;26(4):1252-7
references.pmid: 20817670
references.citation: Front Endocrinol (Lausanne). 2013 Aug 21;4:105
references.pmid: 23970880
references.citation: Chin Med J (Engl). 2009 Sep 5;122(17):1996-2001
references.pmid: 19781384
references.citation: Free Radic Biol Med. 2002 Nov 1;33(9):1221-30
references.pmid: 12398930
references.citation: Free Radic Biol Med. 2009 Mar 15;46(6):719-30
references.pmid: 19162177
references.citation: J Exp Biol. 2004 Aug;207(Pt 18):3221-31
references.pmid: 15299043
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18584-9
references.pmid: 19011099
references.citation: Glia. 2005 Apr 1;50(1):32-47
references.pmid: 15625716
references.citation: Mol Neurobiol. 2008 Feb;37(1):7-38
references.pmid: 18066503
references.citation: J Neurosci Res. 2007 Apr;85(5):1046-56
references.pmid: 17304569
references.citation: Subcell Biochem. 2012;56:85-103
references.pmid: 22116696
references.citation: J Neurochem. 2009 Feb;108(3):563-77
references.pmid: 19054284
references.citation: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8749-54
references.pmid: 17502596