Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n？=？9–14/group; a total of 99) were treated in a factorial design with candesartan 1？mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30？mg/kg IP or GM6001 50？mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3？h of middle cerebral artery occlusion (MCAO) and 21？h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone ( ) and in combination with FeTPPs ( ). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT ( ) and worsened neurologic score ( ). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. 1. Introduction Ischemic stroke, an obstruction of blood flow in a major cerebral vessel, remains a leading cause of adult disability and death in the United States [1]. Because of its complex pathology, a major research and clinical priority is to develop therapeutic interventions in the ischemic brain through the understanding of underlying mechanisms. Ischemia reperfusion leads to a cascade of pathophysiological processes, resulting in further brain damage. Accumulations of free radicals, oxygen/nitrogen species (ROS/RNS), not only increase the susceptibility of brain tissue to reperfusion-induced damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death [2, 3]. As an important component of free radicals, RNS, including peroxynitrite (ONOO–), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia reperfusion results in the production of peroxynitrite in ischemic brain, which triggers numerous molecular cascades and leads to vascular damage. In vitro, peroxynitrite strongly activates matrix metalloproteinases (MMPs) [4, 5]. Peroxynitrite formation on
References
[1]
V. L. Roger, A. S. Go, D. M. Lloyd-Jones, et al., “Heart disease and stroke statistics—2012 update: a report from the American Heart Association,” Circulation, vol. 125, no. 1, pp. e2–e220, 2012.
[2]
Y. Gürsoy-？zdemir, A. Can, and T. Dalkara, “Reperfusion-induced oxidative/nitrativie injury to neurovascular unit after focal cerebral ischemia,” Stroke, vol. 35, no. 6, pp. 1449–1453, 2004.
[3]
J. E. Jung, G. S. Kim, H. Chen et al., “Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection,” Molecular Neurobiology, vol. 41, no. 2-3, pp. 172–179, 2010.
[4]
T. Okamoto, T. Akaike, T. Nagano et al., “Activation of human neutrophil procollagenase by nitrogen dioxide and peroxynitrite: a novel mechanism for procollagenase activation involving nitric oxide,” Archives of Biochemistry and Biophysics, vol. 342, no. 2, pp. 261–274, 1997.
[5]
T. Okamoto, T. Akaike, T. Sawa, Y. Miyamoto, A. van der Vliet, and H. Maeda, “Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation,” The Journal of Biological Chemistry, vol. 276, no. 31, pp. 29596–29602, 2001.
[6]
S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul, “Targets for vascular protection after acute ischemic stroke,” Stroke, vol. 35, no. 9, pp. 2220–2225, 2004.
[7]
T. Sumii and E. H. Lo, “Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats,” Stroke, vol. 33, no. 3, pp. 831–836, 2002.
[8]
B. Q. Zhao, S. Wang, H. Y. Kim et al., “Role of matrix metalloproteinases in delayed cortical responses after stroke,” Nature Medicine, vol. 12, no. 4, pp. 441–445, 2006.
[9]
Y. Suofu, J. Clark, J. Broderick et al., “Peroxynitrite decomposition catalyst prevents matrix metalloproteinase activation and neurovascular injury after prolonged cerebral ischemia in rats,” Journal of Neurochemistry, vol. 115, no. 5, pp. 1266–1276, 2010.
[10]
M. Thiyagarajan, C. L. Kaul, and S. S. Sharma, “Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats,” British Journal of Pharmacology, vol. 142, no. 5, pp. 899–911, 2004.
[11]
S. C. Fagan, A. Kozak, W. D. Hill et al., “Hypertension after experimental cerebral ischemia: candesartan provides neurovascular protection,” Journal of Hypertension, vol. 24, no. 3, pp. 535–539, 2006.
[12]
W. Guan, P. R. Somanath, A. Koza et al., “Vascular protection by angiotensin receptor antagonism involves differential vegf expression in both hemispheres after experimental stroke,” PLoS ONE, vol. 6, no. 9, Article ID e24551, 2011.
[13]
Y. Nishimura, T. Ito, and J. M. Saavedra, “Angiotensin II AT1 blockade normalizes cerebrovascular autoregulation and reduces cerebral ischemia in spontaneously hypertensive rats,” Stroke, vol. 31, no. 10, pp. 2478–2486, 2000.
[14]
G. Reboldi, F. Angeli, C. Cavallini, G. Gentile, G. Mancia, and P. Verdecchia, “Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis,” Journal of Hypertension, vol. 26, no. 7, pp. 1282–1289, 2008.
[15]
H. F. Elewa, A. Kozak, M. H. Johnson, A. Ergul, and S. C. Fagan, “Blood pressure lowering after experimental cerebral ischemia provides neurovascular protection,” Journal of Hypertension, vol. 25, no. 4, pp. 855–859, 2007.
[16]
W. Guan, A. Kozak, A. B. El-Remessy, M. H. Johnson, B. A. Pillai, and S. C. Fagan, “Acute treatment with candesartan reduces early injury after permanent middle cerebral artery occlusion,” Translational Stroke Research, vol. 2, no. 2, pp. 179–185, 2011.
[17]
A. Kozak, A. Ergul, A. B. El-Remessy et al., “Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke,” Stroke, vol. 40, no. 5, pp. 1870–1876, 2009.
[18]
H. Yamakawa, M. Jezova, H. Ando, and J. M. Saavedra, “Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition,” Journal of Cerebral Blood Flow and Metabolism, vol. 23, no. 3, pp. 371–380, 2003.
[19]
M. Hamai, M. Iwai, A. Ide et al., “Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress,” Neuropharmacology, vol. 51, no. 4, pp. 822–828, 2006.
[20]
S. Soliman, T. Ishrat, A. Pillai et al., “Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B,” Journal of Pharmacology and Experimental Therapeutics, vol. 349, no. 3, pp. 444–457, 2014.
[21]
E. C. Sandset, P. M. W. Bath, G. Boysen et al., “The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial,” The Lancet, vol. 377, no. 9767, pp. 741–750, 2011.
[22]
T. Ishrat, B. Pillai, A. Ergul, S. Hafez, and S. C. Fagan, “Candesartan reduces the hemorrhage associated with delayed tissue plasminogen activator treatment in rat embolic stroke,” Neurochemical Research, vol. 38, no. 12, pp. 2668–2677, 2013.
[23]
Y. Murata, A. Rosell, R. H. Scannevin, K. J. Rhodes, X. Wang, and E. H. Lo, “Extension of the thrombolytic time window with minocycline in experimental stroke,” Stroke, vol. 39, no. 12, pp. 3372–3377, 2008.
[24]
L. Zhang, M. Chopp, L. Jia, Y. Cui, M. Lu, and Z. G. Zhang, “Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 11, pp. 1816–1824, 2009.
[25]
J. Montaner, J. Alvarez-Sabín, C. Molina et al., “Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment,” Stroke, vol. 32, no. 8, pp. 1759–1766, 2001.
[26]
A. Rosell, A. Ortega-Aznar, J. Alvarez-Sabín et al., “Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke,” Stroke, vol. 37, no. 6, pp. 1399–1406, 2006.
[27]
E. Z. Longa, P. R. Weinstein, S. Carlson, and R. Cummins, “Reversible middle cerebral artery occlusion without craniectomy in rats,” Stroke, vol. 20, no. 1, pp. 84–91, 1989.
[28]
J. B. Bederson, L. H. Pitts, and M. Tsuji, “Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination,” Stroke, vol. 17, no. 3, pp. 472–476, 1986.
[29]
S. Takizawa, N. Fukuyama, H. Hirabayashi, H. Nakazawa, and Y. Shinohara, “Dynamics of nitrotyrosine formation and decay in rat brain during focal ischemia-reperfusion,” Journal of Cerebral Blood Flow and Metabolism, vol. 19, no. 6, pp. 667–672, 1999.
[30]
A. I. Kelly-Cobbs, R. Prakash, W. Li et al., “Targets of vascular protection in acute ischemic stroke differ in type 2 diabetes,” American Journal of Physiology - Heart and Circulatory Physiology, vol. 304, no. 6, pp. H806–H815, 2013.
[31]
W. Kozak, A. Kozak, M. H. Johnson, H. F. Elewa, and S. C. Fagan, “Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 3, pp. 773–782, 2008.
[32]
U. Dirnagl, U. Lindauer, A. Them et al., “Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo,” Journal of Cerebral Blood Flow and Metabolism, vol. 15, no. 6, pp. 929–940, 1995.
[33]
Y. Yang, L. Ke-Zhou, G. M. Ning, M. L. Wang, and X. X. Zheng, “Dynamics of nitric oxide and peroxynitrite during global brain ischemia/reperfusion in rat hippocampus: NO-sensor measurement and modeling study,” Neurochemical Research, vol. 33, no. 1, pp. 73–80, 2008.
[34]
Y. Gasche, J. Copin, T. Sugawara, M. Fujimura, and P. H. Chan, “Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 12, pp. 1393–1400, 2001.
[35]
M. J. Eliasson, Z. Huang, R. J. Ferrante et al., “Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage,” The Journal of Neuroscience, vol. 19, no. 14, pp. 5910–5918, 1999.
[36]
Y. Gürsoy-？zdemir, H. Bolay, O. Sariba？, and T. Dalkara, “Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia,” Stroke, vol. 31, no. 8, pp. 1974–1981, 2000.
[37]
S. S. Marla, J. Lee, and J. T. Groves, “Peroxynitrite rapidly permeates phospholipid membranes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 26, pp. 14243–14248, 1997.
[38]
G. T. Gobbel, T. Y. Chan, and P. H. Chan, “Nitric oxide- and superoxide-mediated toxicity in cerebral endothelial cells,” Journal of Pharmacology and Experimental Therapeutics, vol. 282, no. 3, pp. 1600–1607, 1997.
[39]
S. Shimizu, R. P. Simon, and S. H. Graham, “Dimethylsulfoxide (DMSO) treatment reduces infarction volume after permanent focal cerebral ischemia in rats,” Neuroscience Letters, vol. 239, no. 2-3, pp. 125–127, 1997.
[40]
S. Nagel, J. Genius, S. Heiland, S. Horstmann, H. Gardner, and S. Wagner, “Diphenyleneiodonium and dimethylsulfoxide for treatment of reperfusion injury in cerebral ischemia of the rat,” Brain Research, vol. 1132, no. 1, pp. 210–217, 2007.
[41]
A. Kleindienst, J. G. Dunbar, R. Glisson, K. Okuno, and A. Marmarou, “Effect of dimethyl sulfoxide on blood-brain barrier integrity following middle cerebral artery occlusion in the rat,” Acta Neurochirurgica, Supplementum, no. 96, pp. 258–262, 2006.
[42]
A. S. Awad, “Effect of combined treatment with curcumin and candesartan on ischemic brain damage in mice,” Journal of Stroke and Cerebrovascular Diseases, vol. 20, no. 6, pp. 541–548, 2011.
[43]
S. Tota, R. Goel, S. D. Pachauri et al., “Effect of angiotensin II on spatial memory, cerebral blood flow, cholinergic neurotransmission, and brain derived neurotrophic factor in rats,” Psychopharmacology, vol. 226, no. 2, pp. 357–369, 2013.
[44]
A. Alhusban, A. Kozak, A. Ergul, and S. C. Fagan, “AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediators,” Journal of Pharmacology and Experimental Therapeutics, vol. 344, no. 2, pp. 348–359, 2013.
