Top

Experimental & Translational Stroke Medicine

Published in:

Open Access 01-12-2009 | Review

Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies

Authors: Jens Minnerup, Sevgi Sevimli, Wolf-Rüdiger Schäbitz

Published in: Experimental & Translational Stroke Medicine | Issue 1/2009

Abstract

G-CSF is widely employed for the treatment of chemotherapy-induced neutropenia. Recently, neuroprotective effects of G-CSF in animal stroke models were discovered including infarct size reduction and enhancement of functional recovery. The underlying mechanisms of action of G-CSF in ischemia appear to be a direct anti-apoptotic activity in neurons and a neurogenesis inducing capacity. Additional effects may be based on the stimulation of new blood-vessel formation, the stimulation of immunocompetence and -modulation as well as on bone marrow mobilization. In addition to a discussion of these mechanisms, we will review the available preclinical studies and analyze their impact on the overall efficacy of G-CSF in experimental stroke.

Available only for authorised users

Burgess AW, Metcalf D: Characterization of a serum factor stimulating the differentiation of myelomonocytic leukemic cells. Int J Cancer 1980, 26: 647–654. 10.1002/ijc.2910260517CrossRefPubMed

Sachs L: The molecular control of blood cell development. Science 1987, 238: 1374–1379. 10.1126/science.3317831CrossRefPubMed

Nicola NA, Begley CG, Metcalf D: Identification of the human analogue of a regulator that induces differentiation in murine leukaemic cells. Nature 1985, 314: 625–628. 10.1038/314625a0CrossRefPubMed

Cavallaro AM, Lilleby K, Majolino I, Storb R, Appelbaum FR, Rowley SD, Bensinger WI: Three to six year follow-up of normal donors who received recombinant human granulocyte colony-stimulating factor. Bone Marrow Transplant 2000, 25: 85–89. 10.1038/sj.bmt.1702072CrossRefPubMed

Frampton JE, Lee CR, Faulds D: Filgrastim. A review of its pharmacological properties and therapeutic efficacy in neutropenia. Drugs 1994, 48: 731–760. 10.2165/00003495-199448050-00007CrossRefPubMed

Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S: Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 2003, 34: 745–751. 10.1161/01.STR.0000057814.70180.17CrossRefPubMed

Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, et al.: The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005, 115: 2083–2098. 10.1172/JCI23559PubMedCentralCrossRefPubMed

Schneider A, Wysocki R, Pitzer C, Kruger C, Laage R, Schwab S, Bach A, Schabitz WR: An extended window of opportunity for G-CSF treatment in cerebral ischemia. BMC Biol 2006, 4: 36. 10.1186/1741-7007-4-36PubMedCentralCrossRefPubMed

Six I, Gasan G, Mura E, Bordet R: Beneficial effect of pharmacological mobilization of bone marrow in experimental cerebral ischemia. Eur J Pharmacol 2003, 458: 327–328. 10.1016/S0014-2999(02)02785-1CrossRefPubMed

10.

Kawada H, Takizawa S, Takanashi T, Morita Y, Fujita J, Fukuda K, Takagi S, Okano H, Ando K, Hotta T: Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation 2006, 113: 701–710. 10.1161/CIRCULATIONAHA.105.563668CrossRefPubMed

11.

Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H: Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 2004, 110: 1847–1854. 10.1161/01.CIR.0000142616.07367.66CrossRefPubMed

12.

Chopp M, Li Y: Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002, 1: 92–100. 10.1016/S1474-4422(02)00040-6CrossRefPubMed

13.

Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A: Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003, 425: 968–973. 10.1038/nature02069CrossRefPubMed

14.

Ono K, Yoshihara K, Suzuki H, Tanaka KF, Takii T, Onozaki K, Sawada M: Preservation of hematopoietic properties in transplanted bone marrow cells in the brain. J Neurosci Res 2003, 72: 503–507. 10.1002/jnr.10588CrossRefPubMed

15.

Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y, Urabe T: Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 2006, 26: 402–413. 10.1038/sj.jcbfm.9600195CrossRefPubMed

16.

Solaroglu I, Cahill J, Tsubokawa T, Beskonakli E, Zhang JH: Granulocyte colony-stimulating factor protects the brain against experimental stroke via inhibition of apoptosis and inflammation. Neurol Res 2009, 31: 167–172. 10.1179/174313209X393582CrossRefPubMed

17.

Park HK, Chu K, Lee ST, Jung KH, Kim EH, Lee KB, Song YM, Jeong SW, Kim M, Roh JK: Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage. Brain Res 2005, 1041: 125–131. 10.1016/j.brainres.2004.11.067CrossRefPubMed

18.

Dayer AG, Cleaver KM, Abouantoun T, Cameron HA: New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. J Cell Biol 2005, 168: 415–427. 10.1083/jcb.200407053PubMedCentralCrossRefPubMed

19.

Luzzati F, De Marchis S, Fasolo A, Peretto P: Neurogenesis in the caudate nucleus of the adult rabbit. J Neurosci 2006, 26: 609–621. 10.1523/JNEUROSCI.4371-05.2006CrossRefPubMed

20.

Jung KH, Chu K, Lee ST, Kang L, Kim SU, Kim M, Roh JK: G-CSF protects human cerebral hybrid neurons against in vitro ischemia. Neurosci Lett 2006, 394: 168–173. 10.1016/j.neulet.2005.10.040CrossRefPubMed

21.

Pandya NM, Dhalla NS, Santani DD: Angiogenesis--a new target for future therapy. Vascul Pharmacol 2006, 44: 265–274. 10.1016/j.vph.2006.01.005CrossRefPubMed

22.

Slevin M, Kumar P, Gaffney J, Kumar S, Krupinski J: Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential. Clin Sci (Lond) 2006, 111: 171–183. 10.1042/CS20060049CrossRef

23.

Arenillas JF, Sobrino T, Castillo J, Davalos A: The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med 2007, 9: 205–212. 10.1007/s11936-007-0014-5CrossRefPubMed

24.

Hayashi T, Deguchi K, Nagotani S, Zhang H, Sehara Y, Tsuchiya A, Abe K: Cerebral ischemia and angiogenesis. Curr Neurovasc Res 2006, 3: 119–129. 10.2174/156720206776875902CrossRefPubMed

25.

Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM: Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994, 25: 1794–1798.CrossRefPubMed

26.

Lee ST, Chu K, Jung KH, Ko SY, Kim EH, Sinn DI, Lee YS, Lo EH, Kim M, Roh JK: Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res 2005, 1058: 120–128. 10.1016/j.brainres.2005.07.076CrossRefPubMed

27.

Taguchi A, Wen Z, Myojin K, Yoshihara T, Nakagomi T, Nakayama D, Tanaka H, Soma T, Stern DM, Naritomi H, et al.: Granulocyte colony-stimulating factor has a negative effect on stroke outcome in a murine model. Eur J Neurosci 2007, 26: 126–133. 10.1111/j.1460-9568.2007.05640.xCrossRefPubMed

28.

Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U: Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 2005, 6: 775–786. 10.1038/nrn1765CrossRefPubMed

29.

Becker KJ, Kindrick DL, Lester MP, Shea C, Ye ZC: Sensitization to brain antigens after stroke is augmented by lipopolysaccharide. J Cereb Blood Flow Metab 2005, 25: 1634–1644. 10.1038/sj.jcbfm.9600160PubMedCentralCrossRefPubMed

30.

Schwartz M, Kipnis J: Protective autoimmunity and neuroprotection in inflammatory and noninflammatory neurodegenerative diseases. J Neurol Sci 2005, 233: 163–166. 10.1016/j.jns.2005.03.014CrossRefPubMed

31.

Yilmaz G, Arumugam TV, Stokes KY, Granger DN: Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation 2006, 113: 2105–2112. 10.1161/CIRCULATIONAHA.105.593046CrossRefPubMed

32.

Hartung T, Von Aulock S, Schneider C, Faist E: How to leverage an endogenous immune defense mechanism: the example of granulocyte colony-stimulating factor. Crit Care Med 2003, 31: S65-S75. 10.1097/00003246-200301001-00010CrossRefPubMed

33.

Gibson CL, Jones NC, Prior MJ, Bath PM, Murphy SP: G-CSF suppresses edema formation and reduces interleukin-1beta expression after cerebral ischemia in mice. J Neuropathol Exp Neurol 2005, 64: 763–769. 10.1097/01.jnen.0000179196.10032.ddCrossRefPubMed

34.

Loddick SA, Rothwell NJ: Neuroprotective effects of human recombinant interleukin-1 receptor antagonist in focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 1996, 16: 932–940. 10.1097/00004647-199609000-00017CrossRefPubMed

35.

Sevimli S, Diederich K, Strecker JK, Schilling M, Klocke R, Nikol S, Kirsch F, Schneider A, Schabitz WR: Endogenous brain protection by granulocyte-colony stimulating factor after ischemic stroke. Exp Neurol 2009, 217: 328–335. 10.1016/j.expneurol.2009.03.018CrossRefPubMed

36.

O'Collins VE, Macleod MR, Donnan GA, Horky LL, Worp BH, Howells DW: 1,026 experimental treatments in acute stroke. Ann Neurol 2006, 59: 467–477. 10.1002/ana.20741CrossRefPubMed

37.

Recommendations for standards regarding preclinical neuroprotective and restorative drug development Stroke 1999, 30: 2752–2758.

38.

Gibson CL, Bath PM, Murphy SP: G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 2005, 25: 431–439. 10.1038/sj.jcbfm.9600033CrossRefPubMed

39.

Yanqing Z, Yu-Min L, Jian Q, Bao-Guo X, Chuan-Zhen L: Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. Brain Res 2006, 1098: 161–169. 10.1016/j.brainres.2006.02.140CrossRefPubMed

40.

Lan X, Qu H, Yao W, Zhang C: Granulocyte-colony stimulating factor inhibits neuronal apoptosis in a rat model of diabetic cerebral ischemia. Tohoku J Exp Med 2008, 216: 117–126. 10.1620/tjem.216.117CrossRefPubMed

41.

Zhao LR, Singhal S, Duan WM, Mehta J, Kessler JA: Brain repair by hematopoietic growth factors in a rat model of stroke. Stroke 2007, 38: 2584–2591. 10.1161/STROKEAHA.106.476457CrossRefPubMed

42.

Philip M, Benatar M, Fisher M, Savitz SI: Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke 2009, 40: 577–581. 10.1161/STROKEAHA.108.524330CrossRefPubMed

43.

Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M: Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 2001, 32: 2433–2438. 10.1161/hs1001.096009CrossRefPubMed

44.

Macleod MR, O'Collins T, Howells DW, Donnan GA: Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004, 35: 1203–1208. 10.1161/01.STR.0000125719.25853.20CrossRefPubMed

45.

Macleod MR, O'Collins T, Horky LL, Howells DW, Donnan GA: Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 2005, 25: 713–721. 10.1038/sj.jcbfm.9600064CrossRefPubMed

46.

Sena E, Wheble P, Sandercock P, Macleod M: Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke 2007, 38: 388–394. 10.1161/01.STR.0000254462.75851.22CrossRefPubMed

47.

Minnerup J, Heidrich J, Wellmann J, Rogalewski A, Schneider A, Schabitz WR: Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke 2008, 39: 1855–1861. 10.1161/STROKEAHA.107.506816CrossRefPubMed

48.

Zhao LR, Berra HH, Duan WM, Singhal S, Mehta J, Apkarian AV, Kessler JA: Beneficial effects of hematopoietic growth factor therapy in chronic ischemic stroke in rats. Stroke 2007, 38: 2804–2811. 10.1161/STROKEAHA.107.486217CrossRefPubMed

49.

Grotta JC: Acute stroke therapy at the millennium: consummating the marriage between the laboratory and bedside. The Feinberg lecture. Stroke 1999, 30: 1722–1728.CrossRefPubMed

Title: Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies
Authors: Jens Minnerup
Sevgi Sevimli
Wolf-Rüdiger Schäbitz
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Experimental & Translational Stroke Medicine / Issue 1/2009
Electronic ISSN: 2040-7378
DOI: https://doi.org/10.1186/2040-7378-1-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2009

Erythropoietin: a multimodal neuroprotective agent

Animal models of focal brain ischemia

Long term immunologic consequences of experimental stroke and mucosal tolerance

Time to overcome the translational roadblock: Introducing a new open access stroke journal

Experimental models for analysis of oligodendrocyte pathophysiology in stroke

Models of autoimmune demyelination in the central nervous system: on the way to translational medicine