Objectives: The goal of this study was to measure the impact of simvastatin and
atorvastatin treatment on blood brain barrier (BBB) integrity after
experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was induced in
27 male Wistar rats by stereotactic injection of100mL
of autologous blood into the striatum. Rats were divided into three groups (n= 9/group): 1) oral
treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin,
or 3) phosphate buffered saline
daily starting 24-hours post-ICH and continuing daily for the next 3 days. On
the fourth day, the animals underwent magnetic resonance imaging (MRI) for
measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed
and immunohistology or Western blotting was performed. Results: MRI data for animals receiving simvastatin treatment
showed significantly reduced BBB dysfunction and improved CBF in the ICH rim
compared to controls (P<0.05) 4 days after ICH. Simvastatin also significantly reduced
edema (T2) in the rim at 4 days after ICH (P<0.05). Both statin-treated groups demonstrated increased occludin and
endothelial barrier antigen levels within the vessel walls, indicating better preservation
of BBB function (P<0.05) and increased number of blood vessels (P<0.05). Conclusions: Simvastatin treatment
administered acutely after ICH protects BBB integrity as measured by MRI and
correlative immunohistochemistry. There was also evidence of improved CBF and
reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend
by MRI measurement.
Cite this paper
D. Yang, R. Knight, Y. Han, K. Karki, J. Zhang, M. Chopp and D. Seyfried, "Statins Protect the Blood Brain Barrier Acutely after Experimental Intracerebral Hemorrhage," Journal of Behavioral and Brain Science, Vol. 3 No. 1, 2013, pp. 100-106. doi: 10.4236/jbbs.2013.31010.
 R. F. Keep, J. Xiang, S. R. Ennis, A. Andjelkovic, Y. Hua, G. Xi, et al., “Blood-Brain Barrier Function in Intracerebral Hemorrhage,” Acta Neurochirurgica Supplement, Vol. 105, 2008, pp. 73-77.
 G. Y. Yang, A. L. Betz, T. L. Chenevert, J. A. Brunberg and J. T. Hoff, “Experimental Intracerebral Hemorrhage: Relationship between Brain Edema, Blood Flow, and Blood-Brain Barrier Permeability in Rats,” Journal of Neurosurgery, Vol. 81, No. 1, 1994, pp. 93-102.
 R. Thiex and S. E. Tsirka, “Brain Edema after Intracerebral Hemorrhage: Mechanisms, Treatment Options, Management Strategies, and Operative Indications,” Neurosurgical Focus, Vol. 22, No. 5, 2007, p. E6.
 K. R. Lee, N. Kawai, S. Kim, O. Sagher and J. T. Hoff, “Mechanisms of Edema Formation after Intracerebral Hemorrhage: Effects of Thrombin on Cerebral Blood Flow, Blood-Brain Barrier Permeability, and Cell Survival in a Rat Model,” Journal of Neurosurgery, Vol. 86, No. 2, 1997, pp. 272-278. doi:10.3171/jns.1997.86.2.0272
 Z. Karwacki, P. Kowianski, M. Witkowska, M. Karwacka, J. Dziewiatkowski and J. Morys, “The Pathophysiology of Intracerebral Haemorrhage,” Folia Morphologica, Vol. 65, No. 4, 2006, pp. 295-300.
 G. Y. Chang, “Hematoma Growth Is a Determinant of Mortality and Poor Outcome after Intracerebral Hemorrhage,” Neurology, Vol. 68, No. 6, 2007, pp. 471-472.
 J. Broderick, S. Connolly, E. Feldmann, D. Hanley, C. Kase, D. Krieger, M. May-berg, L. Morgenstern, C. S. Ogilvy, P. Vespa and M. Zuccarrello, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline from the American Heart Association/American Stroke Association Stroke/ Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group,” Circulation, Vol. 116, No. 16, 2007, pp. e391-413.
 M. Takemoto and J. K. Liao, “Pleiotropic Effects of 3-hydroxy-3-methylglutaryl Co-Enzyme a Reductase Inhibitors,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 21, No. 11, 2001, pp. 1712-1719.
 J. Chen, Z. G. Zhang and Y. Li, “Statins Induce Angiogenesis, Neurogenesis, and Synaptogenesis after Stroke,” Annals of Neurology, Vol. 53, No. 6, 2003, pp. 743-751.
 E. F. Wible and D. T. Laskowitz, “Statins in Traumatic Brain Injury,” Neurotherapeutics, Vol. 7, No. 1, 2010, pp. 62-73. doi:10.1016/j.nurt.2009.11.003
 H. Wu, D. Lu, H. Jiang, Y. Xiong, C. Qu, B. Li, et al., “Simvastatin-Mediated Upregulation of vegf and bdnf, Activation of the pi3k/akt Pathway, and Increase of Neurogenesis Are Associated with Therapeutic Improvement after Traumatic Brain Injury,” Journal of Neurotrauma, Vol. 25, No. 2, 2008, pp. 130-139.
 D. Yang, R. A. Knight, Y. Han, K. Karki, J. Zhang, C. Ding, et al., “Vascular Recovery Promoted by Atorvastatin and Simvastatin after Experimental Intracerebral Hemorrhage: Magnetic Resonance Imaging and Histological Study,” Journal of Neurosurgery, Vol. 114, No. 4, 2011, pp. 1135-1142. doi:10.3171/2010.7.JNS10163
 K. Karki, R. A. Knight, Y. Han, D. Yang, J. Zhang, K. A. Ledbetter, et al., “Simvastatin and Atorvastatin Improve Neurological Outcome after Experimental Intracerebral Hemorrhage,” Stroke, Vol. 40, No. 10, 2009, pp. 33843389. doi:10.1161/STROKEAHA.108.544395
 R. A. Knight, Y. Han, T. N. Nagaraja, P. Whitton, J. Ding, M. Chopp, et al., “Temporal MRI Assessment of Intracerebral Hemorrhage in Rats,” Stroke, Vol. 39, No. 9, 2008, pp. 2596-2602.
 D. Seyfried, Y. Han, D. Lu, J. Chen, A. Bydon and M. Chopp, “Improvement in Neurological Outcome after Administration of Atorvastatin Following Experimental Intracerebral Hemorrhage in Rats,” Journal of Neurosurgery, Vol. 101, No. 1, 2004, pp. 104-107.
 D. M. Seyfried, Y. Han, D. Yang, J. Ding, L. H. Shen, S. Savant-Bhonsale, et al., “Localization of Bone Marrow Stromal Cells to the Injury Site after Intracerebral Hemorrhage in Rats,” Journal of Neurosurgery, Vol. 112, No. 2, 2010, pp. 329-335. doi:10.3171/2009.2.JNS08907
 D. S. Williams, J. A. Detre, J. S. Leigh and A. P. Koretsky, “Magnetic Resonance Imaging of Perfusion Using Spin Inversion of Arterial Water,” Proceedings of the National Academy of Sciences USA, Vol. 89, No. 1, 1992, pp. 212-216. doi:10.1073/pnas.89.1.212
 J. R. Ewing, Q. Jiang, M. Boska, Z. G. Zhang, S. L. Brown, G. H. Li, et al., “T1 and Magnetization Transfer at 7 Tesla in Acute Ischemic Infarct in the Rat,” Magnetic Resonance in Medicine, Vol. 41, No. 4, 1999, pp. 696705.
 G. Brix, L. R. Schad, M. Deimling and W. J. Lorenz, “Fast and Precise t1 Imaging Using a Tomrop Sequence,” Magnetic Resonance Imaging, Vol. 8, No. 4, 1990, pp. 351-356. doi:10.1016/0730-725X(90)90041-Y
 B. Lin and M. D. Ginsberg, “Quantitative Assessment of the Normal Cerebral Microvasculature by Endothelial Barrier Antigen (EBA) Immunohistochemistry: Application to Focal Cerebral Ischemia,” Brain Research, Vol. 865, No. 2, 2000, pp. 237-244.
 K. H. Jung, K. Chu, S. W. Jeong, S. Y. Han, S. T. Lee, J. Y. Kim, et al., “Hmgcoa Reductase Inhibitor, Atorvastatin, Promotes Sensorimotor Recovery, Suppressing Acute Inflammatory Reaction after Experimental Intracerebral Hemorrhage,” Stroke, Vol. 35, No. 7, 2004, pp. 17441749. doi:10.1161/01.STR.0000131270.45822.85
 N. S. Naval, T. A. Abdelhak, N. Urrunaga, P. Zeballos and M. A. Mirski, “An Association of Prior Statin Use with Decreased Perihematomal Edema,” Neurocritical Care, Vol. 8, No. 1, 2008, pp. 13-18.
 N. S. Naval, T. A. Abdelhak, P. Zeballos, N. Urrunaga and M. A. Mirski, “Prior Statin Use Reduces Mortality in Intracerebral Hemorrhage,” Neurocritical Care, Vol. 8, No. 1, 2008, pp. 6-12. doi:10.1007/s12028-007-0080-2
 E. FitzMaurice, L. Wendell, R. Snider, K. Schwab, R. Chanderraj, C. Kinnecom, et al., “Effect of Statins on Intracerebral Hemorrhage Outcome and Recurrence,” Stroke, Vol. 39, No. 7, 2008, pp. 2151-2154.
 H. Tapia-Perez, M. Sanchez-Aguilar, J. G. Torres-Corzo, I. Rodriguez-Leyva, D. Gonzalez-Aguirre, A. GordilloMoscoso, et al., “Use of Statins for the Treatment of Spontaneous Intracerebral Hemorrhage: Results of a Pilot Study,” Central European Neurosurgery, Vol. 70, No. 1, 2009, pp. 15-20. doi:10.1055/s-0028-1082064
 R. Eichel, S. T. Khoury, T. Ben-Hur, M. Keidar, R. Paniri and R. R. Leker, “Prior Use of Statins and Outcome in Patients with Intracerebral Haemorrhage,” European Journal of Neurology, Vol. 17, No. 1, 2010, pp. 78-83.
 L. B. Goldstein, P. Amarenco, M. Szarek, A. Callahan III, M. Hennerici, H. Sille-sen, et al., “Hemorrhagic Stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Study,” Neurology, Vol. 70, No. 24, 2008, pp. 2364-2370.
 C. L. MacLellan, G. Silasi, C. C. Poon, C. L. Edmundson, R. Buist, J. Peeling, et al., “Intracerebral Hemorrhage Models in Rat: Comparing Collagenase to Blood Infusion,” Journal of Cerebral Blood Flow & Metabolism, Vol. 28, No. 3, 2008, pp. 516-525.
 E. Steed, M. S. Balda and K. Matter, “Dynamics and Functions of Tight Junctions,” Trends in Cell Biology, Vol. 20, No. 3, 2010, pp. 142-149.
 M. Furuse, T. Hirase, M. Itoh, A. Nagafuchi, S. Yonemura, S. Tsukita, et al., “Occludin: A Novel Integral Membrane Protein Localizing at Tight Junctions,” Journal of Cell Biology, Vol. 123, No. 6, 1993, pp. 17771788. doi:10.1083/jcb.123.6.1777
 S. J. Bolton, D. C. Anthony and V. H. Perry, “Loss of the Tight Junction Proteins Occludin and Zonula Occludens1 from Cerebral Vascular Endothelium during Neutrophil-Induced Blood-Brain Barrier Breakdown in Vivo,” Neuroscience, Vol. 86, No. 4, 1998, pp. 1245-1257.
 R. C. Brown and T. P. Davis, “Hypoxia/Aglycemia Alters Expression of Occludin and Actin in Brain Endothelial Cells,” Biochemical and Biophysical Research Communications, Vol. 327, No. 4, 2005, pp. 1114-1123.
 J. Krupinski, J. Kaluza, P. Kumar, S. Kumar and J. M. Wang, “Role of Angiogenesis in Patients with Cerebral Ischemic Stroke,” Stroke, Vol. 25, No. 9, 1994, pp. 17941798. doi:10.1161/01.STR.25.9.1794
 T. Hayashi, N. Noshita, T. Sugawara and P. H. Chan, “Temporal Profile of Angiogenesis and Expression of Related Genes in the Brain after Ischemia,” Journal of Cerebral Blood Flow & Metabolism, Vol. 23, No. 2, 2003, pp. 166-180. doi:10.1097/00004647-200302000-00004
 M. Endres and U. Laufs, “Effects of Statins on Endothelium and Signaling Mechanisms,” Stroke, Vol. 35, No. 11, 2004, pp. 2708-2711.
 A. Zacco, J. Togo, K. Spence, A. Ellis, D. Lloyd, S. Furlong, et al., “3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase Inhibitors Protect Cortical Neurons from Excitotoxicity,” Journal of Neuroscience, Vol. 23, No. 35, 2003, pp. 11104-11111.