This Article Full Text Full Text (PDF) All Versions of this Article: 34/1/157    most recent 01.STR.0000048213.18751.52v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawashima, S. Articles by Yokoyama, M. Search for Related Content PubMed PubMed Citation Articles by Kawashima, S. Articles by Yokoyama, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Statins Stroke Related Collections Cardiovascular Pharmacology Animal models of human disease Acute Stroke Syndromes Other Stroke Treatment - Medical

(Stroke. 2003;34:157.)
© 2003 American Heart Association, Inc.

Original Contributions

HMG-CoA Reductase Inhibitor Has Protective Effects Against Stroke Events in Stroke-Prone Spontaneously Hypertensive Rats

Seinosuke Kawashima, MD; Tomoya Yamashita, MD; Yoichi Miwa, MD; Masanori Ozaki, MD; Masayuki Namiki, MD; Tetsuaki Hirase, MD; Nobutaka Inoue, MD; Ken-ichi Hirata, MD Mitsuhiro Yokoyama, MD

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Reprint requests to Seinosuke Kawashima, MD, Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp

Background and Purpose— Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur.

Methods— We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed.

Results— At 14 weeks of age, the incidence (13±3% versus 37±8%; P<0.01) and the size of stroke (1.6±0.2 versus 2.2±0.1 arbitrary units; P<0.01) were significantly decreased by cerivastatin, although blood pressure and plasma cholesterol levels were not different. Moreover, stroke-associated symptoms and early mortality of SHR-SP were markedly reduced in the statin-treated group (mortality at the age of 15 weeks: 15% versus 50%; P<0.05). Statin treatment significantly reduced superoxide production from nonstroke parenchyma of brain and infiltration of inflammatory cells to the stroke lesions.

Conclusions— Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.

Key Words: mortality • rats, inbred SHR • statins • stroke • superoxides

This article has been cited by other articles:

				L. B. Goldstein, P. Amarenco, J. Zivin, M. Messig, I. Altafullah, A. Callahan, M. Hennerici, M. J. MacLeod, H. Sillesen, R. Zweifler, et al. Statin Treatment and Stroke Outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial Stroke, November 1, 2009; 40(11): 3526 - 3531. [Abstract] [Full Text] [PDF]

				A. A. Rabinstein Statins Prevent Stroke Recurrences... But Can They Improve Stroke Outcome? Stroke, November 1, 2009; 40(11): 3413 - 3414. [Full Text] [PDF]

				R. M. Clarke, A. Lyons, F. O'Connell, B. F. Deighan, C. E. Barry, N. G. Anyakoha, A. Nicolaou, and M. A. Lynch A Pivotal Role for Interleukin-4 in Atorvastatin-associated Neuroprotection in Rat Brain J. Biol. Chem., January 25, 2008; 283(4): 1808 - 1817. [Abstract] [Full Text] [PDF]

				M. Shimamura, N. Sato, M. Sata, H. Kurinami, D. Takeuchi, K. Wakayama, T. Hayashi, H. Iida, and R. Morishita Delayed Postischemic Treatment With Fluvastatin Improved Cognitive Impairment After Stroke in Rats Stroke, December 1, 2007; 38(12): 3251 - 3258. [Abstract] [Full Text] [PDF]

				T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure Stroke, November 1, 2007; 38(11): 3016 - 3022. [Abstract] [Full Text] [PDF]

				J. Alvarez-Sabin, R. Huertas, M. Quintana, M. Rubiera, P. Delgado, M. Ribo, C. A. Molina, and J. Montaner Prior Statin Use May Be Associated With Improved Stroke Outcome After Tissue Plasminogen Activator Stroke, March 1, 2007; 38(3): 1076 - 1078. [Abstract] [Full Text] [PDF]

				J. Hallenbeck, G. del Zoppo, T. Jacobs, A. Hakim, S. Goldman, U. Utz, A. Hasan, and for the Immunomodulation Workshop Participants Immunomodulation Strategies for Preventing Vascular Disease of the Brain and Heart: Workshop Summary Stroke, December 1, 2006; 37(12): 3035 - 3042. [Abstract] [Full Text] [PDF]

				M. Feletou and P. M. Vanhoutte Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture) Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H985 - H1002. [Abstract] [Full Text] [PDF]

				M. Nozawa, K.-i. Sugimoto, M. Ohmori, H. Ando, and A. Fujimura Dosing Time-Dependent Effect of Temocapril on the Mortality of Stroke-Prone Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 176 - 181. [Abstract] [Full Text] [PDF]

				M. D. Napoli and F. Papa C-Reactive Protein and Cerebral Small-Vessel Disease: An Opportunity to Reassess Small-Vessel Disease Physiopathology? Circulation, August 9, 2005; 112(6): 781 - 785. [Full Text] [PDF]

				M. S.V. Elkind, A. C. Flint, R. R. Sciacca, and R. L. Sacco Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality Neurology, July 26, 2005; 65(2): 253 - 258. [Abstract] [Full Text] [PDF]

				S. Nagotani, T. Hayashi, K. Sato, W. Zhang, K. Deguchi, I. Nagano, M. Shoji, and K. Abe Reduction of Cerebral Infarction in Stroke-Prone Spontaneously Hypertensive Rats by Statins Associated With Amelioration of Oxidative Stress Stroke, March 1, 2005; 36(3): 670 - 672. [Abstract] [Full Text] [PDF]

				H. Shibata, T. Nabika, H. Moriyama, J. Masuda, and S. Kobayashi Correlation of NO Metabolites and 8-Iso-Prostaglandin F2a With Periventricular Hyperintensity Severity Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1659 - 1663. [Abstract] [Full Text] [PDF]

				K.-H. Jung, K. Chu, S.-W. Jeong, S.-Y. Han, S.-T. Lee, J.-Y. Kim, M. Kim, and J.-K. Roh HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes Sensorimotor Recovery, Suppressing Acute Inflammatory Reaction After Experimental Intracerebral Hemorrhage Stroke, July 1, 2004; 35(7): 1744 - 1749. [Abstract] [Full Text] [PDF]