1Department of Physiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
2Ph.D. Student, Department of Physiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
3Associate Professor, Department of Physiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
4M.Sc. Student, Department of Physiology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
Background & Aims: Stroke is the third leading cause of death. Oxidative stress has a principal role in the complications of stroke. Due to this fact and the antioxidant effects of ascorbic acid, this study was designed to evaluate the effect of ascorbic acid on reduction of stroke complications in a permanent model of middle cerebral artery (MCA) occlusion in male rats. Methods: In this experimental study, the rats were divided into 3 groups of control, ascorbic acid, and surgicalsham. Stroke wasinduced by cauterization of MCA. The animals' brain wassliced and stained using tetrazolium chloride (TTC) 48 hours after stroke induction. Then, infarction volume was determined using image processing software. In addition, behavioral tests, such as neurologic deficits, were evaluated 24 and 48 hours afterstroke induction. Data were statistically analyzed using One-way ANOVA test. Results: The infarct volume significantly reduced in the ascorbic acid treated group in comparison with control group (P < 0.010). Moreover, blood-brain barrier (BBB) breakdown, brain edema volume (P < 0.001), and the level of matrix metallopeptidase-9 (MMP-9) (P < 0.050) significantly reduced following treatment by ascorbic acid. Neurologic deficits, which were assessed using the Bederson Grading System, showed relative improvement in the ascorbic acid treated group (P < 0.050). Conclusion:Thisstudy showed that ascorbic acid, due to its neuroprotective effects, can significantly reduce the complications ofstroke.
Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol 2007; 6(2): 182-7.
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009; 8(4): 355-69.
Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003; 2(1): 43-53.
Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22(9): 391-7.
Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma 2000; 17(10): 871-90.
Heo JH, Han SW, Lee SK. Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 2005; 39(1): 51-70.
Schmidley JW. Free radicals in central nervous system ischemia. Stroke 1990; 21(7): 1086-90.
Faraji F, Ranjbar A, Eshrati B, Talaie A, Shafie N, Pirasteh S. Comparing the oxidative stress indexes of CVA patients with control group. J Arak Univ Med Sci 2008; 11(3): 109-16. [In Persian].
Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 1997; 75(10-11): 1149-63.
Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 2001; 21(1): 2-14.
Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology 2008; 55(3): 310-8.
Segura T, Calleja S, Jordan J. Recommendations and treatment strategies for the management of acute ischemic stroke. Expert Opin Pharmacother 2008; 9(7): 1071-85.
Wang CX, Shuaib A. Neuroprotective effects of free radical scavengers in stroke. Drugs Aging 2007; 24(7): 537-46.
Zamani M, Soleimani M, Golab F, Mohamadzadeh F, Mehdizadeh M, Katebi M. Neuro protective effects of adenosine receptor agonist coadministration with ascorbic acid on CA1 hippocampus in a mouse model of ischemia reperfusion injury. Metab Brain Dis 2013; 28(3): 367-74.
Huang J, Agus DB, Winfree CJ, Kiss S, Mack WJ, McTaggart RA, et al. Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A 2001; 98(20): 11720-4.
Mack WJ, Mocco J, Ducruet AF, Laufer I, King RG, Zhang Y, et al. A cerebroprotective dose of intravenous citrate/sorbitol-stabilized dehydroascorbic acid is correlated with increased cerebral ascorbic acid and inhibited lipid peroxidation after murine reperfused stroke. Neurosurgery 2006; 59(2): 383-8.
Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, et al. Antioxidant profile and early outcome in stroke patients. Stroke 2000; 31(10): 2295-300.
Sanchez-Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF, Martin A. Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke. Stroke 2004; 35(1): 163-8.
Ranjan A, Theodore D, Haran RP, Chandy MJ. Ascorbic acid and focal cerebral ischaemia in a primate model. Acta Neurochir (Wien) 1993; 123(1-2): 87-91.
Allahtavakoli M, Rezaee H, Kamrany N, Shamsizadeh A, Moloudi R, Amin F. Effect of ascorbic acid on infarct volume and neurological deficits after the embolic model of stroke in rat. J Rafsanjan Univ Med Sci 2009; 8(1): 49-58. [In Persian].
Slivka A, Murphy E, Horrocks L. Cerebral edema after temporary and permanent middle cerebral artery occlusion in the rat. Stroke 1995; 26(6): 1061-5.
Fraser PA. The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med 2011; 51(5): 967-77.
Jiao H, Wang Z, Liu Y, Wang P, Xue Y. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 2011; 44(2): 130-9.
Bemeur C, Ste-Marie L, Desjardins P, Vachon L, Butterworth RF, Hazell AS, et al. Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat. Neurochem Int 2005; 46(5): 399-407.
Orbe J, Rodriguez JA, Calvo A, Grau A, Belzunce MS, Martinez-Caro D, et al. Vitamins C and E attenuate plasminogen activator inhibitor-1 (PAI-1) expression in a hypercholesterolemic porcine model of angioplasty. Cardiovasc Res 2001; 49(2): 484-92.
Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB, III, et al. Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol 1995; 15(1): 156-65.
Rodriguez JA, Grau A, Eguinoa E, Nespereira B, Perez-Ilzarbe M, Arias R, et al. Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesterolemia in vivo and in vitro. Atherosclerosis 2002; 165(1): 33-40.
McCormick J, Barry SP, Sivarajah A, Stefanutti G, Townsend PA, Lawrence KM, et al. Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J 2006; 20(12): 2115-7.
Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. Tissue plasminogen activator (tPA) increase neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nature Medicine 1998; 4: 228-31.
Nassar NN, Abdelsalam RM, Abdel-Rahman AA, Abdallah DM. Possible involvement of oxidative stress and inflammatory mediators in the protective effects of the early preconditioning window against transient global ischemia in rats. Neurochem Res 2012; 37(3): 614-21.
Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 2009; 7: 97.
Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 2001; 53(1): 135-59.
Castillo J, Davalos A, Noya M. Progression of ischaemic stroke and excitotoxic aminoacids. Lancet 1997; 349(9045): 79-83.
Bond M, Chase AJ, Baker AH, Newby AC. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc Res 2001; 50(3): 556-65.
Agus DB, Gambhir SS, Pardridge WM, Spielholz C, Baselga J, Vera JC, et al. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest 1997; 100(11): 2842-8.
Lam DK, Daniel PM. The influx of ascorbic acid into the rat's brain. Q J Exp Physiol 1986; 71(3): 483-9.
Patterson JW. The diabetogenic effect of dehydroascorbic acid. Endocrinology 1949; 45(3): 344.
Polidori MC, Pratico D, Ingegni T, Mariani E, Spazzafumo L, del Sindaco P, et al. Effects of vitamin C and aspirin in ischemic stroke-related lipid peroxidation: results of the AVASAS (Aspirin Versus Ascorbic acid plus Aspirin in Stroke) Study. Biofactors 2005; 24(1-4): 265-74.
Ullegaddi R, Powers HJ, Gariballa SE. Antioxidant supplementation with or without B-group vitamins after acute ischemic stroke: a randomized controlled trial. JPEN J Parenter Enteral Nutr 2006; 30(2): 108-14.