Acute statin treatment improves recovery after experimental intracerebral hemorrhage


Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8); 10, 20 and 40 mg/kg simvastatin-treated groups (n = 8); and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.

Share and Cite:

Yang, D. , Zhang, J. , Han, Y. , James, E. , Chopp, M. and Seyfried, D. (2013) Acute statin treatment improves recovery after experimental intracerebral hemorrhage. World Journal of Neuroscience, 3, 69-75. doi: 10.4236/wjns.2013.32010.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Donnan, G.A., Fisher, M., Macleod, M. and Davis, S.M. (2008) Stroke. Lancet, 371, 1612-1623. doi:10.1016/S0140-6736(08)60694-7
[2] Feigin, V.L. (2005) Stroke epidemiology in the developing world. Lancet, 365, 2160-2161. doi:10.1016/S0140-6736(05)66755-4
[3] Bhalla, A. and Hargroves, D. (2008) Does early medical intervention has a role in the management of intracerebral haemorrhage? International Journal of Clinical Practice, 62, 633-641. doi:10.1111/j.1742-1241.2007.01691.x
[4] Seyfried, D., Han, Y., Lu, D., Chen, J., Bydon, A. and Chopp, M. (2004) Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats. Journal of Neurosurgery, 101, 104-107. doi:10.3171/jns.2004.101.1.0104
[5] Yang, D., Knight, R.A., Han, Y., Karki, K., Zhang, J., Ding, C., Chopp, M. and Seyfried, D.M. (2011) Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: Magnetic resonance imaging and histological study. Journal of Neurosurgery, 114, 1135-1142. doi:10.3171/2010.7.JNS10163
[6] Seyfried, D., Ding, J., Han, Y., Li, Y., Chen, J. and Chopp, M. (2006) Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. Journal of Neurosurgery, 104, 313-318. doi:10.3171/jns.2006.104.2.313
[7] Otero, L., Zurita, M., Bonilla, C., Aguayo, C., Rico, M.A., Rodriguez, A. and Vaquero, J. (2012) Allogeneic bone marrow stromal cell transplantation after cerebral hemorrhage achieves cell transdifferentiation and modulates endogenous neurogenesis. Cytotherapy, 14, 34-44. doi:10.3109/14653249.2011.608349
[8] Cotena, S., Piazza, O. and Tufano, R. (2008) The use of erythtropoietin in cerebral diseases. Panminerva Medica, 50, 185-192.
[9] Lu, D., Qu, C., Goussev, A., Jiang, H., Lu, C., Schallert, T., Mahmood, A., Chen, J., Li, Y. and Chopp, M. (2007) Statins increase neurogenesis in the dentate gyrus, reduce delayed neuronal death in the hippocampal CA3 region, and improve spatial learning in rat after traumatic brain injury. Journal of Neurotrauma, 24, 1132-1146. doi:10.1089/neu.2007.0288
[10] Zhang, L., Chopp, M., Jia, L., Cui, Y., Lu, M. and Zhang, Z.G. (2009) Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. Journal of Cerebral Blood Flow & Metabolism, 29, 1816-1824. doi:10.1038/jcbfm.2009.105
[11] Jung, K.H., Chu, K., Jeong, S.W., Han, S.Y., Lee, S.T., Kim, J.Y., Kim, M. and Roh, J.K. (2004) HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke, 35, 1744-1749. doi:10.1161/01.STR.0000131270.45822.85
[12] Chopp, M. and Li, Y. (2008) Treatment of stroke and intracerebral hemorrhage with cellular and pharmacological restorative therapies. Acta Neurochirurgica Supplement, 105, 79-83. doi:10.1007/978-3-211-09469-3_16
[13] Katsuki, H. Exploring neuroprotective drug therapies for intracerebral hemorrhage. Journal of Pharmacological Sciences, 114, 366-378. doi:10.1254/jphs.10R05CR
[14] Cui, J.J., Wang, D., Gao, F. and Li, Y.R. (2012) Effects of atorvastatin on pathological changes in brain tissue and plasma MMP-9 in rats with intracerebral hemorrhage. Cell Biochemistry and Biophysics, 62, 87-90. doi:10.1007/s12013-011-9264-7
[15] Urbich, C., Dernbach, E., Zeiher, A.M. and Dimmeler, S. (2002) Double-edged role of statins in angiogenesis signaling. Circulation Research, 90, 737-744. doi:10.1161/01.RES.0000014081.30867.F8
[16] Fonseca, A.C., Resende, R., Oliveira, C.R. and Pereira, C.M. (2010) Cholesterol and statins in Alzheimer’s disease: Current controversies. Experimental Neurology, 223, 282-293. doi:10.1016/j.expneurol.2009.09.013
[17] Goldstein, L.B., Amarenco, P., Szarek, M., Callahan, A., 3rd, Hennerici, M., Sillesen, H., Zivin, J.A. and Welch, K.M. (2008) Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study. Neurology, 70, 2364-2370. doi:10.1212/01.wnl.0000296277.63350.77
[18] Yang, S., Song, S., Hua, Y., Nakamura, T., Keep, R.F. and Xi, G. (2008) Effects of thrombin on neurogenesis after intracerebral hemorrhage. Stroke, 39, 2079-2084. doi:10.1161/STROKEAHA.107.508911
[19] Zhang, L., Zhang, Z.G., Ding, G.L., Jiang, Q., Liu, X., Meng, H., Hozeska, A., Zhang, C., Li, L., Morris, D., Zhang, R.L., Lu, M. and Chopp, M. (2005) Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation, 112, 3486-3494. doi:10.1161/CIRCULATIONAHA.104.516757
[20] Zhang, L., Schallert, T., Zhang, Z.G., Jiang, Q., Arniego, P., Li, Q., Lu, M. and Chopp, M. (2002) A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. Journal of Neuroscience Methods, 117, 207-214. doi:10.1016/S0165-0270(02)00114-0
[21] Chen, J., Li, Y., Wang, L., Zhang, Z., Lu, D., Lu, M. and Chopp, M. (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke, 32, 1005-1011. doi:10.1161/01.STR.32.4.1005
[22] Valiente, R.A., de Miranda-Alves, M.A., Silva, G.S., Gomes, D.L., Brucki, S.M., Rocha, M.S. and Massaro, A.R. (2008) Clinical features associated with early hospital arrival after acute intracerebral hemorrhage: Challenges for new trials. Cerebrovascular Diseases, 26, 404-408. doi:10.1159/000151681
[23] Karki, K., Knight, R.A., Han, Y., Yang, D., Zhang, J., Ledbetter, K.A., Chopp, M. and Seyfried, D.M. (2009) Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke, 40, 3384-3389. doi:10.1161/STROKEAHA.108.544395
[24] Amarenco, P., Bogousslavsky, J., Callahan, A., 3rd, Goldstein, L.B., Hennerici, M., Rudolph, A.E., Sillesen, H., Simunovic, L., Szarek, M., Welch, K.M. and Zivin, J.A. (2006) High-dose atorvastatin after stroke or transient ischemic attack. The New England Journal of Medicine, 355, 549-559. doi:10.1056/NEJMoa061894
[25] Karam, J.G., Loney-Hutchinson, L. and McFarlane, S.I. (2008) High-dose atorvastatin after stroke or transient ischemic attack: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. Journal of the CardioMetabolic Syndrome, 3, 68-69. doi:10.1111/j.1559-4572.2008.07967.x
[26] Tirschwell, D.L., Smith, N.L., Heckbert, S.R., Lemaitre, R.N., Longstreth Jr., W.T. and Psaty, B.M. (2004) Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology, 63, 1868-1875. doi:10.1212/01.WNL.0000144282.42222.DA
[27] Pfrieger, F.W. (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cellular and Molecular Life Sciences, 60, 1158-1171.
[28] Indraswari, F., Wang, H., Lei, B., James, M.L., Kernagis, D., Warner, D.S., Dawson, H.N. and Laskowitz, D.T. Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: A translational approach. Journal of Neurotrauma, 29, 1388-1400. doi:10.1089/neu.2011.2117
[29] Sironi, L., Banfi, C., Brioschi, M., Gelosa, P., Guerrini, U., Nobili, E., Gianella, A., Paoletti, R., Tremoli, E. and Cimino, M. (2006) Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiology of Disease, 22, 445-451. doi:10.1016/j.nbd.2005.12.004
[30] Chen, J., Zhang, Z.G., Li, Y., Wang, Y., Wang, L., Jiang, H., Zhang, C., Lu, M., atakowski, M., Feldkamp, C. and Chipp, M. (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Annals of Neurology, 53, 743-751.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.