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Aging and disease    2018, Vol. 9 Issue (3) : 453-466     DOI: 10.14336/AD.2017.1130
Orginal Article |
APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats
Yan Tao1,2, Venkat Poornima2, Chopp Michael2,3, Zacharek Alex2, Yu Peng2, Ning Ruizhuo2,4, Qiao Xiaoxi5, Kelley Mark R.6, Chen Jieli2,*
1Gerontology Institute, Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neurotrauma Neurorepair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China
2Department of Neurology, Henry Ford hospital, Detroit, MI, USA
3Department of Physics, Oakland University, Rochester, MI, USA
4Department of Neurology, First Hospital Harbin, Harbin, China.
5Department of Ophthalmology, Henry Ford Hospital, Detroit, MI, USA
6Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
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APX3330 is a selective inhibitor of APE1/Ref-1 redox activity. In this study, we investigate the therapeutic effects and underlying mechanisms of APX3330 treatment in type one diabetes mellitus (T1DM) stroke rats. Adult male Wistar rats were induced with T1DM and subjected to transient middle cerebral artery occlusion (MCAo) and treated with either PBS or APX3330 (10mg/kg, oral gavage) starting at 24h after MCAo, and daily for 14 days. Rats were sacrificed at 14 days after MCAo and, blood brain barrier (BBB) permeability, ischemic lesion volume, immunohistochemistry, cell death assay, Western blot, real time PCR, and angiogenic ELISA array were performed. Compared to PBS treatment, APX3330 treatment of stroke in T1DM rats significantly improves neurological functional outcome, decreases lesion volume, and improves BBB integrity as well as decreases total vessel density and VEGF expression, while significantly increases arterial density in the ischemic border zone (IBZ). APX3330 significantly increases myelin density, oligodendrocyte number, oligodendrocyte progenitor cell number, synaptic protein expression, and induces M2 macrophage polarization in the IBZ of T1DM stroke rats. Compared to PBS treatment, APX3330 treatment significantly decreases plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 and matrix metalloproteinase 9 (MMP9) and receptor for advanced glycation endproducts expression in the ischemic brain of T1DM stroke rats. APX3330 treatment significantly decreases cell death and MMP9 and PAI-1 gene expression in cultured primary cortical neurons subjected to high glucose and oxygen glucose deprivation, compared to untreated control cells. APX3330 treatment increases M2 macrophage polarization and decreases inflammatory factor expression in the ischemic brain as well as promotes neuroprotective and neurorestorative effects after stroke in T1DM rats.

Keywords Stroke      Type 1 Diabetes Mellitus      APX3330      neuroprotection      neurorestoration     
Corresponding Authors: Chen Jieli   
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SZ and JZ denote equal first authorship contribution.

Issue Date: 05 June 2018
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Yan Tao
Venkat Poornima
Chopp Michael
Zacharek Alex
Yu Peng
Ning Ruizhuo
Qiao Xiaoxi
Kelley Mark R.
Chen Jieli
Cite this article:   
Yan Tao,Venkat Poornima,Chopp Michael, et al. APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats[J]. Aging and disease, 2018, 9(3): 453-466.
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Figure 1.  APX3330 improves stroke outcome and decreases ischemic burden and BBB permeability in T1DM rats. Treatment with APX3330 significantly improves neurological functional outcome after stroke in T1DM rats as indicated by (A) Foot-fault test and (B) modified neurological severity score (mNSS). APX3330 treatment also significantly decreases (C) ischemic lesion volume and (D) BBB disruption after stroke in T1DM rats.
Figure 2.  APX3330 increases arterial density and decreases dysfunctional angiogenesis after stroke in T1DM rats. APX3330 significantly increases (A) arterial density and decreases (B) vascular density and (C) VEGF expression in the ischemic border zone after stroke in T1DM rats, as indicated by α-smooth muscle actin (α-SMA), Von Willebrand Factor (vWF) and vascular endothelial growth factor (VEGF) immunostaining and quantification data respectively.
Figure 3.  APX3330 significantly promotes white matter remodeling after stroke in T1DM rats. APX3330 significantly increases (A) myelin density (Luxol fast blue), (B) synaptic protein expression (Synaptophysin), (C) oligodendrocyte cell number (CNPase), and (D) oligodendrocyte progenitor cell (NG2) number in the ischemic border zone of T1DM stroke rats.
Figure 4.  APX3330 treatment significantly promotes M2 macrophage polarization in the ischemic brain of T1DM stroke rats. APX3330 significantly decreases (A) ED1 (M1 macrophage marker, and significantly increases (B) CD163 (M2 macrophage marker) in the ischemic border zone of T1DM stroke rats.
Figure 5.  APX3330 treatment significantly decreases inflammatory factors after stroke in T1DM rats. (A) An ELISA array was employed to measure inflammatory protein expression in the ischemic brain. APX3330 significantly decreases (B) plasminogen activator inhibitor type 1 (PAI-1), (C) monocyte chemotactic protein-1 (MCP1) and (D) MMP9 compared to control T1DM stroke rats.
Figure 6.  APX3330 treatment decreases inflammatory factor expression in the ischemic brain of T1DM stroke rats and significantly decreases primary cortical neurons cell death and inflammatory factor expression after stroke. (A) Western blot assay shows that APX3330 significantly decreases ischemic brain tissue expression of MMP9 and RAGE compared to control T1DM stroke rats. APX3330 treatment significantly decreases (B) primary cortical neuron cell death compared to control (untreated) cells as measured by LDH assay and (C) significantly decreases MMP9 and PAI-1 gene expression in primary cortical neurons subjected to high glucose and oxygen glucose deprivation, when compared to control (untreated) cells.
[1] Mast H, Thompson JL, Lee SH, Mohr JP, Sacco RL (1995). Hypertension and diabetes mellitus as determinants of multiple lacunar infarcts. Stroke, 26: 30-33
[2] Li W, Prakash R, Kelly-Cobbs AI, Ogbi S, Kozak A, El-Remessy AB, et al. (2010). Adaptive cerebral neovascularization in a model of type 2 diabetes: relevance to focal cerebral ischemia. Diabetes, 59: 228-235
[3] Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC (2001). Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke, 32: 2426-2432
[4] Nakaji K, Ihara M, Takahashi C, Itohara S, Noda M, Takahashi R, et al. (2006). Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke, 37: 2816-2823
[5] Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M (2011). White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke, 42: 445-452
[6] Singh B, Singh V, Krishnan A, Koshy K, Martinez JA, Cheng C, et al. (2014). Regeneration of diabetic axons is enhanced by selective knockdown of the PTEN gene. Brain, 137: 1051-1067
[7] Chen J, Venkat P, Zacharek A, Chopp M (2014). Neurorestorative Therapy for Stroke. Front Hum Neurosci, 8
[8] Rosenberg GA, Navratil M, Barone F, Feuerstein G (1996). Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab, 16: 360-366
[9] Wallin A, Sjogren M, Edman A, Blennow K, Regland B (2000). Symptoms, vascular risk factors and blood-brain barrier function in relation to CT white-matter changes in dementia. Eur Neurol, 44: 229-235
[10] Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, et al. (2001). Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci, 21: 7724-7732
[11] Barile GR, Schmidt AM (2007). RAGE and its ligands in retinal disease. Curr Mol Med, 7: 758-765
[12] Maillard-Lefebvre H, Boulanger E, Daroux M, Gaxatte C, Hudson BI, Lambert M (2009). Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases. Rheumatology (Oxford), 48: 1190-1196
[13] Ye X, Chopp M, Liu X, Zacharek A, Cui X, Yan T, et al. (2011). Niaspan reduces high-mobility group box 1/receptor for advanced glycation endproducts after stroke in type-1 diabetic rats. Neuroscience, 190: 339-345
[14] Emsley HC, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, et al. (2003). An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J Neuroimmunol, 139: 93-101
[15] Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, et al. (2009). Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke, 40: 1849-1857
[16] Iadecola C, Anrather J (2011). The immunology of stroke: from mechanisms to translation. Nat Med, 17: 796-808
[17] Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. (2012). Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke, 43: 3063-3070
[18] Yilmaz G, Granger DN (2010). Leukocyte recruitment and ischemic brain injury. Neuromolecular Med, 12: 193-204
[19] Kelley MR, Georgiadis MM, Fishel ML (2012). APE1/Ref-1 Role in Redox Signaling: Translational Applications of Targeting the Redox Function of the DNA Repair/Redox Protein APE1/Ref-1. Curr Mol Pharmacol, 5: 36-53
[20] Thakur S, Sarkar B, Cholia RP, Gautam N, Dhiman M, Mantha AK (2014). APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. Exp Mol Med, 46: e106
[21] J Cereb Blood Flow MetabKelley MR, Fehrenbacher JC (2017). Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage. Neural Regen Res, 12: 72-74
[22] Shah F, Logsdon D, Messmann RA, Fehrenbacher JC, Fishel ML, Kelley MR (2017). Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol, 1: 19
[23] Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, et al. (2004). Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke, 35: 987-991
[24] Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y (2010). The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation, 7: 74
[25] Ning R, Chopp M, Zacharek A, Yan T, Zhang C, Roberts C, et al. (2014). Neamine induces neuroprotection after acute ischemic stroke in type one diabetic rats. Neuroscience, 257: 76-85
[26] Geng J, Wang L, Qu M, Song Y, Lin X, Chen Y, et al. (2017). Endothelial progenitor cells transplantation attenuated blood-brain barrier damage after ischemia in diabetic mice via HIF-1α. Stem Cell Res Ther, 8: 163
[27] Xiao H, Gu Z, Wang G, Zhao T (2013). The Possible Mechanisms Underlying the Impairment of HIF-1α Pathway Signaling in Hyperglycemia and the Beneficial Effects of Certain Therapies. Int J Med Sci, 10: 1412-1421
[28] Yan J, Zhang Z, Shi H (2012). HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol Life Sci, 69: 115-128
[29] Ergul A, Abdelsaid M, Fouda AY, Fagan SC (2014). Cerebral neovascularization in diabetes: implications for stroke recovery and beyond. J Cereb Blood Flow Metab, 34: 553-563
[30] Reeson P, Tennant KA, Gerrow K, Wang J, Weiser Novak S, Thompson K, et al. (2015). Delayed inhibition of VEGF signaling after stroke attenuates blood-brain barrier breakdown and improves functional recovery in a comorbidity-dependent manner. J Neurosci, 35: 5128-5143
[31] Jiang A, Gao H, Kelley MR, Qiao X (2011). Inhibition of APE1/Ref-1 redox activity with APX3330 blocks retinal angiogenesis in vitro and in vivo. Vision Res, 51: 93-100
[32] Like AA, Rossini AA (1976). Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science, 193: 415-417
[33] Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. (2001). Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke, 32: 1005-1011
[34] Chen H, Chopp M, Zhang ZG, Garcia JH (1992). The effect of hypothermia on transient middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab, 12: 621-628
[35] Rogers DC, Campbell CA, Stretton JL, Mackay KB (1997). Correlation Between Motor Impairment and Infarct Volume After Permanent and Transient Middle Cerebral Artery Occlusion in the Rat. Stroke, 28: 2060-2066
[36] Schaar KL, Brenneman MM, Savitz SI (2010). Functional assessments in the rodent stroke model. Exp Transl Stroke Med, 2: 13
[37] Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR (1990). A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab, 10: 290-293
[38] Yan T, Venkat P, Ye X, Chopp M, Zacharek A, Ning R, et al. (2014). HUCBCs Increase Angiopoietin 1 and Induce Neurorestorative Effects after Stroke in T1DM Rats. CNS Neurosci Ther, 20: 935-944
[39] Yan T, Venkat P, Chopp M, Zacharek A, Ning R, Cui Y, et al. (2015). Neurorestorative Therapy of Stroke in Type 2 Diabetes Mellitus Rats Treated With Human Umbilical Cord Blood Cells. Stroke, 46: 2599-2606
[40] Chen J, Ning R, Zacharek A, Cui C, Cui X, Yan T, et al. (2016). MiR-126 Contributes to Human Umbilical Cord Blood Cell-Induced Neurorestorative Effects After Stroke in Type-2 Diabetic Mice. Stem cells, 34: 102-113
[41] Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, et al. (2003). Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol, 53: 743-751
[42] Ueno Y, Chopp M, Zhang L, Buller B, Liu Z, Lehman NL, et al. (2012). Axonal outgrowth and dendritic plasticity in the cortical peri-infarct area after experimental stroke. Stroke, 43: 2221-2228
[43] Taylor AM, Blurton-Jones M, Rhee SW, Cribbs DH, Cotman CW, Jeon NL (2005). A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nat Methods, 2: 599-605
[44] Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, et al. (2011). Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. Exp Neurol, 232: 299-308
[45] Hori S, Ohtsuki S, Hosoya K, Nakashima E, Terasaki T (2004). A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem, 89: 503-513
[46] Megherbi SE, Milan C, Minier D, Couvreur G, Osseby GV, Tilling K, et al. (2003). Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from the European BIOMED Stroke Project. Stroke, 34: 688-694
[47] Sahin I, Alkan A, Keskin L, Cikim A, Karakas HM, Firat AK, et al. (2008). Evaluation of in vivo cerebral metabolism on proton magnetic resonance spectroscopy in patients with impaired glucose tolerance and type 2 diabetes mellitus. J Diabetes Complications, 22: 254-260
[48] Leys D, Englund E, Del Ser T, Inzitari D, Fazekas F, Bornstein N, et al. (1999). White matter changes in stroke patients. Relationship with stroke subtype and outcome. Eur Neurol, 42: 67-75
[49] Arai K, Lo EH (2009). Oligovascular signaling in white matter stroke. Biol Pharm Bull, 32: 1639-1644
[50] Mandai K, Matsumoto M, Kitagawa K, Matsushita K, Ohtsuki T, Mabuchi T, et al. (1997). Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia. Neuroscience, 77: 849-861
[51] Chen J, Chopp M (2006). Neurorestorative treatment of stroke: Cell and pharmacological approaches. NeuroRx, 3: 466-473
[52] Venkat P, Chopp M, Chen J (2017). Blood-Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke. J Am Heart Assoc, 6
[53] Kimura-Ohba S, Yang Y (2016). Oxidative DNA Damage Mediated by Intranuclear MMP Activity Is Associated with Neuronal Apoptosis in Ischemic Stroke. Oxid Med Cell Longev, 2016: 9
[54] Gao D, Huang T, Jiang X, Hu S, Zhang L, Fei Z (2014). Resveratrol protects primary cortical neuron cultures from transient oxygen-glucose deprivation by inhibiting MMP-9. Mol Med Rep, 9: 2197-2204
[55] Trost S, Pratley R, Sobel B (2006). Impaired fibrinolysis and risk for cardiovascular disease in the metabolic syndrome and type 2 diabetes. Curr Diab Rep, 6: 47-54
[56] Grant PJ (2007). Diabetes mellitus as a prothrombotic condition. J Intern Med, 262: 157-172
[57] Jankun J, Al-Senaidy A, Skrzypczak-Jankun E (2012). Can inactivators of plasminogen activator inhibitor alleviate the burden of obesity and diabetes? (Review). Int J Mol Med, 29: 3-11
[58] Kaji H (2016). Adipose Tissue-Derived Plasminogen Activator Inhibitor-1 Function and Regulation. Compr Physiol, 6: 1873-1896
[59] Mertens I, Verrijken A, Michiels JJ, Van der Planken M, Ruige JB, Van Gaal LF (2006). Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome. Int J Obes, 30: 1308-1314
[60] Vinagre I, Sanchez-Quesada JL, Sanchez-Hernandez J, Santos D, Ordonez-Llanos J, De Leiva A, et al. (2014). Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of LDL subfraction phenotype. Cardiovasc Diabetol, 13: 34
[61] Menegazzo L, Poncina N, Albiero M, Menegolo M, Grego F, Avogaro A, et al. (2015). Diabetes modifies the relationships among carotid plaque calcification, composition and inflammation. Atherosclerosis, 241: 533-538
[62] Nazir N, Siddiqui K, Al-Qasim S, Al-Naqeb D (2014). Meta-analysis of diabetic nephropathy associated genetic variants in inflammation and angiogenesis involved in different biochemical pathways. BMC Med Genet, 15: 103
[63] Bose S, Cho J (2013). Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Arch Pharm Res, 36: 1039-1050
[64] Morancho A, Ma F, Barcelo V, Giralt D, Montaner J, Rosell A (2015). Impaired vascular remodeling after endothelial progenitor cell transplantation in MMP9-deficient mice suffering cortical cerebral ischemia. J Cereb Blood Flow Metab, 35: 1547-1551
[65] Chaturvedi M, Kaczmarek L (2014). MMP-9 Inhibition: a Therapeutic Strategy in Ischemic Stroke. Mol Neurobiol, 49: 563-573
[66] Jalal FY, Yang Y, Thompson J, Lopez AC, Rosenberg GA (2012). Myelin loss associated with neuroinflammation in hypertensive rats. Stroke, 43: 1115-1122
[67] Schmidt AM, Yan SD, Yan SF, Stern DM (2001). The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest, 108: 949-955
[68] Journal of Clinical InvestigationHassid BG, Nair MN, Ducruet AF, Otten ML, Komotar RJ, Pinsky DJ, et al. (2009). Neuronal RAGE expression modulates severity of injury following transient focal cerebral ischemia. J Clin Neurosci, 16: 302-306
[69] Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ, et al. (2008). The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci, 28: 12023-12031
[70] Perego C, Fumagalli S, De Simoni M-G (2013). Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury. J Vis Exp: 50605
[71] Jin Q, Cheng J, Liu Y, Wu J, Wang X, Wei S, et al. (2014). Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun, 40: 131-142
[72] Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009). Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci, 29: 13435-13444
[73] Ylä-Herttuala S, Lipton BA, Rosenfeld ME, Särkioja T, Yoshimura T, Leonard EJ, et al. (1991). Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci U S A, 88: 5252-5256
[74] Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C (2002). Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab, 22: 308-317
[75] Jin X, Yao T, Zhou Z, Zhu J, Zhang S, et al. (2015). Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway. Biomed Res Int, 2015: 12
[76] Dong X, Song Y-N, Liu W-G, Guo X-L (2009). MMP-9, a Potential Target for Cerebral Ischemic Treatment. Curr Neuropharmacol, 7: 269-275
[77] Stetler RA, Gao Y, Leak RK, Weng Z, Shi Y, Zhang L, et al. (2016). APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proc Natl Acad Sci U S A, 113: E3558-3567
[78] Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, et al. (2000). VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest, 106: 829-838
[79] Yan T, Venkat P, Chopp M, Zacharek A, Ning R, Roberts C, et al. (2016). Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats. Stroke, 47: 2850-2858
[80] Kolluru GK, Bir SC, Kevil CG (2012). Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med, 2012: 918267
[81] Prakash R, Li W, Qu Z, Johnson MA, Fagan SC, Ergul A (2013). Vascularization pattern after ischemic stroke is different in control versus diabetic rats: relevance to stroke recovery. Stroke, 44: 2875-2882
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