Reduction of Brain Injury After Stroke in Hyperglycemic Rats via Fasudil Pretreatment

Expand
  • (1. Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; 2. Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming 650500, China; 3. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China)

Online published: 2019-12-07

Abstract

Diabetes is usually associated with cerebrovascular disease, especially stroke. In practice, fasudil is widely accepted to be applied for the treatment of vascular disease. This article demonstrates the study concentrating on the effects of fasudil pretreatment on the prognosis of diabetic stroke. 250—300 g Sprague- Dawley rats were randomly divided into three groups, non-diabetic stroke group, diabetic stroke group, and fasudil pretreatment group. The rats of diabetes group were treated with intraperitoneal injection of streptozotocin (60 mg/kg), in the meantime the same dose of citrate buffer was injected into those of the control group. The rats of the fasudil group received daily fasudil intraperitoneal injection at 10 mg/kg for three consecutive weeks. After four weeks, all the rats of the experimental group were treated with middle cerebral artery occlusion for 90 min. After sacrifice, the fresh brain samples were collected for following experiments, including infarct volume, edema volume, blood-brain barrier (BBB), which were detected by immunohistochemistry. Inflammatory factors were examined by real-time polymerase chain reaction (RT-PCR) using tissue Ribonucleic Acid (RNA). The concentration of blood glucose is 15 mmol/L or more, which proved that the diabetes model was a success. Fasudil pretreatment decreases the percentage of stroke mortality of diabetes from 43.75% to 31.25%, while the infarction volume decreases from 52.95% ± 12.7% to 45.97% ± 6.7%. Gap formation of tight junction and Immunoglobulin G (IgG) leakage were reduced (P < 0.05), and the expression of inflammatory factors decreases (P < 0.05) in fasudil pretreatment after diabetic stroke. Diabetes aggravates the mortality of cerebral ischemic rats. Prolonged fasudil pretreatment can reduce mortality of diabetic stroke, decrease cerebral infarction volume and undermine inflammatory factors expression, and protect the BBB.

Cite this article

LIU Jianyu (刘健宇), MU Zhihao (木志浩), WANG Liping (王丽萍), WEN Ruoxue (闻若雪), WANG Yongting (王永亭), YANG Guoyuan (杨国源), ZHANG Zhijun (张志君) . Reduction of Brain Injury After Stroke in Hyperglycemic Rats via Fasudil Pretreatment[J]. Journal of Shanghai Jiaotong University(Science), 2019 , 24(6) : 723 -731 . DOI: 10.1007/s12204-019-2127-x

References

[1] SALOMON J A, WANG H D, FREEMAN MK, et al.Healthy life expectancy for 187 countries, 1990-2010:A systematic analysis for the Global Burden DiseaseStudy 2010 [J]. The Lancet, 2012, 380(9859): 2144-2162. [2] KIM A S, CAHILL E, CHENG N T. Global strokebelt: Geographic variation in stroke burden worldwide[J]. Stroke, 2015, 46(12): 3564-3570. [3] STEGMAYR B, ASPLUND K. Diabetes as a risk factorfor stroke: A population perspective [J]. Diabetologia,1995, 38(9): 1061-1068. [4] CAPES S E, HUNT D, MALMBERG K, et al. Stresshyperglycemia and prognosis of stroke in nondiabeticand diabetic patients: A systematic overview [J].Stroke, 2001, 32(10): 2426-2432. [5] ERGUL A, KELLY-COBBS A, ABDALLA M, et al.Cerebrovascular complications of diabetes: focus onstroke [J]. Endocrine, Metabolic & Immune Disorders-Drug Targets, 2012, 12(2): 148-158. [6] PULSINELLIWA, LEVY D E, SIGSBEE B, et al. Increaseddamage after ischemic stroke in patients withhyperglycemia with or without established diabetesmellitus [J]. The American Journal of Medicine, 1983,74(4): 540-544. [7] PUTAALA J, LIEBKIND R, GORDIN D, et al. Diabetesmellitus and ischemic stroke in the young: Clinicalfeatures and long-term prognosis [J]. Neurology,2011, 76(21): 1831-1837. [8] ERGUL A, ELGEBALY M M, MIDDLEMORE M L,et al. Increased hemorrhagic transformation and alteredinfarct size and localization after experimentalstroke in a rat model type 2 diabetes [J]. BMC Neurology,2007, 7: 33. [9] AIR E L, KISSELA B M. Diabetes, the metabolic syndrome,and ischemic stroke: Epidemiology and possiblemechanisms [J]. Diabetes Care, 2007, 30(12): 3131-3140. [10] MART′IN A, ROJAS S, CHAMORRO A, et al. Whydoes acute hyperglycemia worsen the outcome of transientfocal cerebral ischemia? Role of corticosteroids,inflammation, and protein O-glycosylation [J]. Stroke,2006, 37: 1288-1295. [11] KRUYT N D, BIESSELS G J, DEVRIES J H, et al.Hyperglycemia in acute ischemic stroke: Pathophysiologyand clinical management [J]. Nature Reviews Neurology,2010, 6(3): 145-155. [12] MASUMOTO A, MOHRI M, SHIMOKAWA H, et al.Suppression of coronary artery spasm by the Rhokinaseinhibitor fasudil in patients with vasospasticangina [J]. Circulation, 2002, 105(13): 1545-1547. [13] OKAMURA N, SAITO M, MORI A, et al. Vasodilatoreffects of fasudil, a Rho-kinase inhibitor, on retinalarterioles in stroke-prone spontaneously hypertensiverats [J]. Journal of Ocular Pharmacology and Therapeutics,2007, 23(3): 207-212. [14] MIYATA K, SHIMOKAWA H, KANDABASHI T, etal. Rho-kinase is involved in macrophage-mediated formationof coronary vascular lesions in pigs in vivo[J]. Arteriosclerosis, Thrombosis, and Vascular Biology,2000, 20(11): 2351-2358. [15] GOJO A, UTSUNOMIYA K, TANIGUCHI K, etal. The Rho-kinase inhibitor, fasudil, attenuates diabeticnephropathy in streptozotocin-induced diabeticrats [J]. European Journal of Pharmacology, 2007,568(1/2/3): 242-247. [16] LIN G R, CRAIG G P, ZHANG L L, et al. Acute inhibitionof Rho-kinase improves cardiac contractile functionin streptozotocin-diabetic rats [J]. CardiovascularResearch, 2007, 75(1): 51-58. [17] KAWAMURA H, YOKOTE K, ASAUMI S, et al. Highglucose-induced upregulation of osteopontin is mediatedvia Rho/Rho kinase pathway in cultured rat aorticsmooth muscle cells [J]. Arteriosclerosis, Thrombosis,and Vascular Biology, 2004, 24(2): 276-281. [18] REINIGER N, LAU K, MCCALLA D, et al. Deletionof the receptor for advanced glycation end productsreduces glomerulosclerosis and preserves renal functionin the diabetic OVE26 mouse [J]. Diabetes, 2010,59(8): 2043-2054. [19] ZHANG Y, PENG F F, GAO B, et al. Mechanicalstrain-induced RhoA activation requires NADPHoxidase-mediated ROS generation in caveolae [J]. Antioxidants& Redox Signaling, 2010, 13(7): 959-973. [20] GALLE J. Oxidized LDL and its compound lysophosphatidylcholinepotentiate AngII-induced vasoconstrictionby stimulation of RhoA [J]. Journal of theAmerican Society of Nephrology, 2003, 14(6): 1471-1479. [21] CHRISSOBOLIS S, SOBEY C G. Recent evidence foran involvement of Rho-kinase in cerebral vascular disease[J]. Stroke, 2006, 37(8): 2174-2180. [22] DIDION S P, LYNCH C M, BAUMBACH G L, etal. Impaired endothelium-dependent responses and enhancedinfluence of Rho-kinase in cerebral arterioles intype II diabetes [J]. Stroke, 2005, 36(2): 342-347. [23] ARITA R, HATA Y, NAKAO S, et al. Rho kinaseinhibition by fasudil ameliorates diabetes-induced microvasculardamage [J]. Diabetes, 2009, 58(1): 215-226. [24] SRIVASTAVA K, SHAO B L, BAYRAKTUTAN U.PKC-β exacerbates in vitro brain barrier damage inhyperglycemic settings via regulation of RhoA/Rhokinase/MLC2 pathway [J]. Journal of Cerebral BloodFlow & Metabolism, 2013, 33(12): 1928-1936. [25] PEARSON J T, JENKINS M J, EDGLEY A J, et al.Acute Rho-kinase inhibition improves coronary dysfunctionin vivo, in the early diabetic microcirculation[J]. Cardiovascular Diabetology, 2013, 12: 111. [26] SHIN H K, HUANG P L, AYATA C. Rho-kinase inhibitionimproves ischemic perfusion deficit in hyperlipidemicmice [J]. Journal of Cerebral Blood Flow &Metabolism, 2014, 34(2): 284-287. [27] VAN NIEUW AMERONGEN G P, BECKERS C ML, ACHEKAR I D, et al. Involvement of Rho kinasein endothelial barrier maintenance [J]. Arteriosclerosis,Thrombosis, and Vascular Biology, 2007, 27(11): 2332-2339. [28] NIZAMUDEEN Z A, CHAKRABARTI L, SOTTILEV. Exposure to the ROCK inhibitor fasudil promotesgliogenesis of neural stem cells in vitro [J]. Stem CellResearch, 2018, 28: 75-86. [29] GUAN S J, MA Z H, WU Y L, et al. Long-termadministration of fasudil improves cardiomyopathyin streptozotocin-induced diabetic rats [J]. Food andChemical Toxicology, 2012, 50(6): 1874-1882. [30] ALVES M G, OLIVEIRA P F, SOCORRO S, et al.Impact of diabetes in blood-testis and blood-brain barriers:Resemblances and differences [J]. Current DiabetesReviews, 2012, 8(6): 401-412. [31] KRIJNEN P A J, SIMSEK S, NIESSEN H W M.Apoptosis in diabetes [J]. Apoptosis, 2009, 14(12):1387-1388. [32] PRAKASH R, LI W G, QU Z, et al. Vascularizationpattern after ischemic stroke is different in control versusdiabetic rats: Relevance to stroke recovery [J].Stroke, 2013, 44(10): 2875-2882. [33] MU Z H, JIANG Z, LIN X J, et al. Vessel dilationattenuates endothelial dysfunction following middlecerebral artery occlusion in hyperglycemic rats [J].CNS Neuroscience & Therapeutics, 2016, 22(4): 316-324. [34] YAN T, CHOPP M, CHEN J L. Experimental animalmodels and inflammatory cellular changes in cerebralischemic and hemorrhagic stroke [J]. Neuroscience Bulletin,2015, 31(6): 717-734. [35] LIUY, TANGGH, SUNYH, et al.The protective roleof Tongxinluo on blood-brain barrier after ischemiareperfusion brain injury [J]. Journal of Ethnopharmacology,2013, 148(2): 632-639. [36] ZHANG Y Q,WU S J. Effects of fasudil on pulmonaryhypertension in clinical practice [J]. Pulmonary Pharmacology& Therapeutics, 2017, 46: 54-63. [37] HUANG J, LI Y N, TANG Y H, et al. CXCR4 antagonistAMD3100 protects blood-brain barrier integrityand reduces inflammatory response after focal ischemiain mice [J]. Stroke, 2013, 44(1): 190-197. [38] GASCHE Y, COPIN J C, CHAN P H. The role ofmetalloproteinases on blood-brain barrier breakdownafter ischemic stroke [M]//FEUERSTEIN G Z. Inlammationand stroke. Basel, Switzerland: Birkh¨auserBasel, 2001: 265-274. [39] LAZAREVIC-PASTI T, LESKOVAC A, VASIC V.Myeloperoxidase inhibitors as potential drugs [J]. CurrentDrug Metabolism, 2015, 16(3): 168-190. [40] RAKIETEN N, RAKIETEN M L, NADKARNI M R.Studies on the diabetogenic action of streptozotocin(NSC-37917) [J]. Cancer Chemother Rep, 1963, 29:91-98. [41] ZAKRZESKA A, GROMOTOWICZ-POPWSKA A,SZEMRAJ J, et al. Eplerenone reduces arterial thrombosisin diabetic rats [J]. Journal of the Renin-Angiotensin-Aldosterone System, 2015, 16(4): 1085-1094. [42] DEMIRY¨UREK S, KARA A F, C?ELIK A, et al. Effectsof fasudil, a Rho-kinase inhibitor, on myocardialpreconditioning in anesthetized rats [J]. EuropeanJournal of Pharmacology, 2005, 527(1/2/3): 129-140. [43] RIKITAKE Y, KIM H H, HUANG Z H, et al. Inhibitionof Rho kinase (ROCK) leads to increased cerebralblood flow and stroke protection [J]. Stroke, 2005,36(10): 2251-2257. [44] VENNIN C, RATH N, PAJIC M, et al. TargetingROCK activity to disrupt and prime pancreatic cancerfor chemotherapy [J]. Small GTPases, 2017: 1-8. DOI:10.1080/21541248.2017.1345712. [45] ALLEN C, SRIVASTAVA K, BAYRAKTUTAN U.Small GTPase RhoA and its effector Rho kinase mediateoxygen glucose deprivation-evoked in vitro cerebralbarrier dysfunction [J]. Stroke, 2010, 41(9): 2056-2063. [46] THOMPSON B J, RONALDSON P T. Drug deliveryto the ischemic brain [J]. Advances in pharmacology,2014, 71: 165-202. [47] LATOUR L L, KANG D W, EZZEDDINE M A, et al.Early blood-brain barrier disruption in human focalbrain ischemia [J]. Annals of Neurology, 2004, 56(4):468-477. [48] SIMPKINS A N, DIAS C, LEIGH R. Identification ofreversible disruption of the human blood-brain barrierfollowing acute ischemia [J]. Stroke, 2016, 47(9): 2405-2408. [49] GIBSON C L, SRIVASTAVA K, SPRIGG N, et al. Inhibitionof Rho-kinase protects cerebral barrier fromischaemia-evoked injury through modulations of endothelialcell oxidative stress and tight junctions [J].Journal of Neurochemistry, 2014, 129(5): 816-826. [50] FUJIIM, DURIS K, ALTAY O, et al. Inhibition of Rhokinase by hydroxyfasudil attenuates brain edema aftersubarachnoid hemorrhage in rats [J]. NeurochemistryInternational, 2012, 60(3): 327-333. [51] DEJANA E. Endothelial cell-cell junctions: Happytogether [J]. Nature Reviews Molecular Cell Biology,2004, 5(4): 261-270. [52] WISPELWEY B, LESSE A J, HANSEN E J, etal. Haemophilus influenzae lipopolysaccharide-inducedblood brain barrier permeability during experimentalmeningitis in the rat [J]. The Journal of Clinical Investigation,1988, 82(4): 1339-1346. [53] QUAGLIARELLO V J, WISPELWEY B, LONG WJ, et al. Recombinant human interleukin-1 inducesmeningitis and blood-brain barrier injury in the rat:Characterization and comparison with tumor necrosisfactor [J]. The Journal of Clinical Investigation, 1991,87(4): 1360-1366. [54] DELI M A, DESCAMPS L, DEHOUCK M P, et al.Exposure of tumor necrosis factor-α to luminal membraneof bovine brain capillary endothelial cells coculturedwith astrocytes induces a delayed increaseof permeability and cytoplasmic stress fiber formationof actin [J]. Journal of Neuroscience Research, 1995,41(6): 717-726. [55] BANKS W A, KASTIN A J. The interleukins-1α, -1β,and -2 do not acutely disrupt the murine blood-brainbarrier [J]. International Journal of Immunopharmacology,1992, 14(4): 629-636. [56] TARKOWSKI E, ROSENGREN L, BLOMSTRANDC, et al. Intrathecal release of pro- and antiinflammatorycytokines during stroke [J]. Clinical &Experimental Immunology, 1997, 110(3): 492-499. [57] ZHANG W D, SMITH C, SHAPIRO A, et al. Increasedexpression of bioactive chemokines in humancerebromicrovascular endothelial cells and astrocytessubjected to simulated ischemia in vitro [J]. Journalof Neuroimmunology, 1999, 101(2): 148-160. [58] HE Y, XU H S, LIANG L Q, et al. Antiinflammatoryeffect of Rho kinase blockade via inhibition of NF-κB activation in rheumatoid arthritis [J]. Arthritis &Rheumatism, 2008, 58(11): 3366-3376. [59] THORLACIUS K, SLOTTA J E, LASCHKE M W, etal. Protective effect of fasudil, a Rho-kinase inhibitor,on chemokine expression, leukocyte recruitment, andhepatocellular apoptosis in septic liver injury [J]. Journalof Leukocyte Biology, 2006, 79(5): 923-931. [60] CHENG T, PETRAGLIA A L, LI Z, et al. Activatedprotein C inhibits tissue plasminogen activatorinducedbrain hemorrhage [J]. Nature Medicine, 2006,12(11): 1278-1285. [61] ZLOKOVIC B V. Remodeling after stroke [J]. NatureMedicine, 2006, 12(4): 390-391. [62] KEMPURAJ D, THANGAVEL R, SELVAKUMAR G P, et al. Brain and peripheral atypical inflammatorymediators potentiate neuroinflammation and neurodegeneration[J]. Frontiers in Cellular Neuroscience,2017, 11: 216.
Outlines

/