Thymosin β4 Improves Neurological Outcome and Enhances Induced Oligodendrogenesis in the Rat after ICH

DOI: 10.4236/wjns.2014.45043   PDF   HTML   XML   3,278 Downloads   3,757 Views   Citations


Thymosin β4 (Tβ4), a G-actin binding protein, has diverse biological functions. This study tested the effects of Tβ4 on oligodendrogenesis in a rat model of intracerebral hemorrhage (ICH). ICH was induced by stereotactic injection of 100 μm of autologous blood into the striatum in 32 male Wistar rats. The rats were randomly divided into four groups: 1) saline control group (n = 8); 2) 3 mg/kg Tβ4-treated group (n = 8); 3) 6 mg/kg Tβ4-treated group (n = 8); and 4) 12 mg/kg Tβ4treated group (n = 8). Tβ4 or saline was administered intraperitoneally starting at 24 h post ICH and then every 3 days for 4 additional doses. The neurological functional outcome was evaluated by behavioral tests (i.e., modified Neurological Severity Score and corner turn test) at multiple time points after ICH. Animals were sacrificed at 28 days post ICH, and histological studies were completed. Tβ4 treatment improved neurological functional recovery significantly and increased actively proliferating oligodendrocytic progenitor cells and myelinating oligodendrocytes in the ICH-affected brain tissue, compared with the saline-treated group. The high-dose treatment of Tβ4 showed better restorative effects compared with the low-dose treatment. Tβ4 treatment enhanced ICH-induced oligodendrogenesis that may contribute to the enhanced functional recovery after ICH. Further investigation is warranted to determine the associated underlying mechanisms of Tβ4 treatment for ICH.

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Yang, D. , Han, Y. , Chopp, M. and Seyfried, D. (2014) Thymosin β4 Improves Neurological Outcome and Enhances Induced Oligodendrogenesis in the Rat after ICH. World Journal of Neuroscience, 4, 395-405. doi: 10.4236/wjns.2014.45043.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Morgenstern, L.B., Hemphill 3rd, J.C., Anderson, C., Becker, K., Broderick, J.P., Connolly Jr., E.S., Greenberg, S.M., Huang, J.N., MacDonald, R.L., Messe, S.R., Mitchell, P.H., Selim, M. and Tamargo, R.J. (2010) Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke, 41, 2108-2129.
[2] Lee, S.H., Kim, B.J., Ryu, W.S., Kim, C.K., Kim, N., Park, B.J. and Yoon, B.W. (2010) White Matter Lesions and Poor Outcome after Intracerebral Hemorrhage: A Nationwide Cohort Study. Neurology, 74, 1502-1510.
[3] Lok, J., Leung, W., Murphy, S., Butler, W., Noviski, N. and Lo, E.H. (2012) Intracranial Hemorrhage: Mechanisms of Secondary Brain Injury. Acta Neurochirurgica Supplementum, 111, 63-69.
[4] Masumura, M., Hata, R., Nagai, Y. and Sawada, T. (2001) Oligodendroglial Cell Death with DNA Fragmentation in the White Matter under Chronic Cerebral Hypoperfusion: Comparison between Normotensive and Spontaneously Hypertensive Rats. Neuroscience Research, 39, 401-412.
[5] Medana, I.M. and Esiri, M.M. (2003) Axonal Damage: A Key Predictor of Outcome in Human CNS Diseases. Brain, 126, 515-530.
[6] Aguirre, A., Dupree, J.L., Mangin, J.M. and Gallo, V. (2007) A Functional Role for EGFR Signaling in Myelination and Remyelination. Neuroscience Research, 10, 990-1002.
[7] Huff, T., Muller, C.S., Otto, A.M., Netzker, R. and Hannappel, E. (2001) Beta-Thymosins, Small Acidic Peptides with Multiple Functions. The International Journal of Biochemistry & Cell Biology, 33, 205-220.
[8] Safer, D., Sosnick, T.R. and Elzinga, M. (1997) Thymosin Beta 4 Binds Actin in an Extended Conformation and Contacts Both the Barbed and Pointed ends. Biochemistry, 36, 5806-5816.
[9] Sanders, M.C., Goldstein, A.L. and Wang, Y.L. (1992) Thymosin Beta 4 (Fx peptide) Is a Potent Regulator of Actin Polymerization in Living Cells. Proceedings of the National Academy of Sciences, 89, 4678-4682.
[10] Amarenco, P., Bogousslavsky, J., Callahan 3rd, A., 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. New England Journal of Medicine, 355, 549-559.
[11] Malinda, K.M., Sidhu, G.S., Mani, H., Banaudha, K., Maheshwari, R.K., Goldstein, A.L. and Kleinman, H.K. (1999) Thymosin Beta4 Accelerates Wound Healing. Journal of Investigative Dermatology, 113, 364-368.
[12] Bock-Marquette, I., Saxena, A., White, M.D., Dimaio, J.M. and Srivastava, D. (2004) Thymosin Beta4 Activates Integrin-Linked Kinase and Promotes Cardiac Cell Migration, Survival and Cardiac Repair. Nature, 432, 466-472.
[13] Santra, M., Chopp, M., Zhang, Z.G., Lu, M., Santra, S., Nalani, A., Santra, S. and Morris, D.C. (2012) Thymosin Beta 4 Mediates Oligodendrocyte Differentiation by Upregulating p38 MAPK. Glia, 60, 1826-1838.
[14] Smart, N., Risebro, C.A., Melville, A.A., Moses, K., Schwartz, R.J., Chien, K.R. and Riley, P.R. (2007) Thymosin Beta4 Induces Adult Epicardial Progenitor Mobilization and Neovascularization. Nature, 445, 177-182.
[15] Carpintero, P., Anadon, R., Diaz-Regueira, S. and Gomez-Marquez, J. (1999) Expression of Thymosin Beta4 Messenger RNA in Normal and Kainate-Treated Rat Forebrain. Neuroscience, 90, 1433-1444.
[16] Gomez-Marquez, J. and Anadon, R. (2002) The Beta-Thymosins, Small Actin-Binding Peptides Widely Expressed in the Developing and Adult Cerebellum. The Cerebellum, 1, 95-102.
[17] Yang, H., Cheng, X., Yao, Q., Li, J. and Ju, G. (2008) The Promotive Effects of Thymosin Beta4 on Neuronal Survival and Neurite Outgrowth by Upregulating L1 Expression. Neurochemical Research, 33, 2269-2280.
[18] MacLellan, C.L., Langdon, K.D., Churchill, K.P., Granter-Button, S. and Corbett, D. (2009) Assessing Cognitive Function after Intracerebral Hemorrhage in Rats. Behavioural Brain Research, 198, 321-328.
[19] Morris, D.C., Zhang, Z.G., Zhang, J., Xiong, Y., Zhang, L. and Chopp, M. (2012) Treatment of Neurological Injury with Thymosin Beta4. Annals of the New York Academy of Sciences, 1269, 110-116.
[20] Xiong, Y., Zhang, Y., Mahmood, A., Meng, Y., Zhang, Z.G., Morris, D.C. and Chopp, M. (2012) Neuroprotective and Neurorestorative Effects of Thymosin Beta4 Treatment Initiated 6 Hours after Traumatic Brain Injury in Rats. Journal of Neurosurgery, 116, 1081-1092.
[21] Zhang, J., Zhang, Z.G., Morris, D., Li, Y., Roberts, C., Elias, S.B. and Chopp, M. (2009) Neurological Functional Recovery after Thymosin Beta4 Treatment in Mice with Experimental Auto Encephalomyelitis. Neuroscience, 164, 1887-1893.
[22] Knight, R.A., Han, Y., Nagaraja, T.N., Whitton, P., Ding, J., Chopp, M. and Seyfried, D.M. (2008) Temporal MRI Assessment of Intracerebral Hemorrhage in Rats. Stroke, 39, 2596-2602.
[23] 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.
[24] 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.
[25] Xiong, Y., Mahmood, A., Meng, Y., Zhang, Y., Zhang, Z.G., Morris, D.C. and Chopp, M. (2011) Treatment of Traumatic Brain Injury with Thymosin Beta4 in Rats. Journal of Neurosurgery, 114, 102-115.
[26] Morris, D.C., Chopp, M., Zhang, L., Lu, M. and Zhang, Z.G. (2010) Thymosin Beta4 Improves Functional Neurological Outcome in a Rat Model of Embolic Stroke. Neuroscience, 169, 674-682.
[27] 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.
[28] 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.
[29] Keirstead, H.S. and Blakemore, W.F. (1997) Identification of Post-Mitotic Oligodendrocytes Incapable of Remyelination within the Demyelinated Adult Spinal Cord. Journal of Neuropathology Experimental Neurology, 56, 1191-1201.
[30] Wu, Z.H. and Zhao, S.P. (2009) Niacin Promotes Cholesterol Efflux through Stimulation of the PPARgamma-LXRalpha-ABCA1 Pathway in 3T3-L1 Adipocytes. Pharmacology, 84, 282-287.
[31] Aronowski, J. and Zhao, X. (2011) Molecular Pathophysiology of Cerebral Hemorrhage: Secondary Brain Injury. Stroke, 42, 1781-1786.
[32] Crockford, D. (2007) Development of Thymosin Beta4 for Treatment of Patients with Ischemic Heart Disease. Annals of the New York Academy of Sciences, 1112, 385-395.
[33] Mora, C.A., Baumann, C.A., Paino, J.E., Goldstein, A.L. and Badamchian, M. (1997) Biodistribution of Synthetic Thymosin Beta 4 in the Serum, Urine, and Major Organs of Mice. International Journal of Immunopharmacology, 19, 1-8.
[34] Low, T.L. and Goldstein, A.L. (1984) Thymosins: Structure, Function and Therapeutic Applications. Thymus, 6, 27-42.
[35] Sosne, G., Hafeez, S., Greenberry 2nd, A.L. and Kurpakus-Wheater, M. (2002) Thymosin Beta4 Promotes Human Conjunctival Epithelial Cell Migration. Current Eye Research, 24, 268-273.
[36] Sosne, G., Szliter, E.A., Barrett, R., Kernacki, K.A., Kleinman, H. and Hazlett, L.D. (2002) Thymosin Beta 4 Promotes Corneal Wound Healing and Decreases Inflammation in Vivo Following Alkali Injury. Experimental Eye Research, 74, 293-299.
[37] Guarnera, G., De Rosa, A. and Camerini, R. (2007) Thymosin Beta-4 and Venous Ulcers: Clinical Remarks on a European Prospective, Randomized Study on Safety, Tolerability, and Enhancement on Healing. Annals of the New York Academy of Sciences, 1112, 407-412.
[38] Yang, G.Y., Betz, A.L., Chenevert, T.L., Brunberg, J.A. and Hoff, J.T. (1994) Experimental Intracerebral Hemorrhage: Relationship between Brain Edema, Blood Flow, and Blood-Brain Barrier Permeability in Rats. Journal of Neurosurgery, 81, 93-102.
[39] Zhao, X., Song, S., Sun, G., Strong, R., Zhang, J., Grotta, J.C. and Aronowski, J. (2009) Neuroprotective Role of Haptoglobin after Intracerebral Hemorrhage. Journal of Neurosurgery, 29, 15819-15827.
[40] Wagner, K.R. and Dwyer, B.E. (2004) Hematoma Removal, Heme, and Heme Oxygenase Following Hemorrhagic Stroke. Annals of the New York Academy of Sciences, 1012, 237-251.
[41] Wagner, K.R., Sharp, F.R., Ardizzone, T.D., Lu, A. and Clark, J.F. (2003) Heme and Iron Metabolism: Role in Cerebral Hemorrhage. Journal of Cerebral Blood Flow & Metabolism, 23, 629-652.
[42] Zhao, X., Song, S., Sun, G., Zhang, J., Strong, R., Zhang, L., Grotta, J.C. and Aronowski, J. (2011) Cytoprotective Role of Haptoglobin in Brain after Experimental Intracerebral Hemorrhage. Intracerebral Hemorrhage Research, 111, 107-112.
[43] McTigue, D.M. and Tripathi, R.B. (2008) The Life, Death, and Replacement of Oligodendrocytes in the Adult CNS. Journal of Neurosurgery, 107, 1-19.

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