Skip to main content
NeuroRx logoLink to NeuroRx
. 2012 Sep 5;3(4):458–465. doi: 10.1016/j.nurx.2006.08.003

Growth factors and stroke

David A Greenberg 1,, Kunlin Jin 1
PMCID: PMC3593408  PMID: 17012059

Summary

Current options for the treatment of stroke are extremely limited, partly because of the rapidity with which brain cells die when deprived of their blood supply. Several recent studies suggest that growth factors can produce improvement in animal models of stroke, even when administered at postischemic intervals of many hours to days, when conventional neuroprotective approaches are typically futile. Several growth factors can access the brain after systemic administration, making them more attractive as therapeutic agents. Finally, growth factors are key mediators of neurogenesis in the adult brain, which could have a role in brain repair and functional recovery following stroke.

Key Words: Stroke, ischemia, growth factor, neuroprotection, neurogenesis

References

  • 1.Vilcek J. The cytokines: an overview. In: Thomson AW, Lotze MT, editors. The cytokine handbook. 4 ed. San Diego: Academic Press; 2003. pp. 3–18. [Google Scholar]
  • 2.Ren JM, Finklestein SP. Growth factor treatment of stroke. Curr Drug Targets CNS Neurol Disord. 2005;4:121–125. doi: 10.2174/1568007053544101. [DOI] [PubMed] [Google Scholar]
  • 3.Wu D. Neuroprotection in experimental stroke with targeted neurotrophins. NeuroRx. 2005;2:120–128. doi: 10.1602/neurorx.2.1.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Kiprianova I, Schindowski K, von Bohlen, Halbach O, et al. Enlarged infarct volume and loss of BDNF mRNA induction following brain ischemia in mice lacking FGF-2. Exp Neurol. 2004;189:252–260. doi: 10.1016/j.expneurol.2004.06.004. [DOI] [PubMed] [Google Scholar]
  • 5.Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA. Increased severity of cerebral ischemic injury in vascular endothelial growth factor-B (VEGFB)-deficient mice. J Cereb Blood Flow Metab. 2004;24:1146–1152. doi: 10.1097/01.WCB.0000134477.38980.38. [DOI] [PubMed] [Google Scholar]
  • 6.Wang Y, Kilic E, Kilic U, et al. VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain. 2005;128:52–63. doi: 10.1093/brain/awh325. [DOI] [PubMed] [Google Scholar]
  • 7.Yamashita K, Wiessner C, Lindholm D, Thoenen H, Hossmann KA. Post-occlusion treatment with BDNF reduces infarct size in a model of permanent occlusion of the middle cerebral artery in rat. Metab Brain Dis. 1997;12:271–280. doi: 10.1007/BF02674671. [DOI] [PubMed] [Google Scholar]
  • 8.Schabitz WR, Berger C, Kollmar R, et al. Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia. Stroke. 2004;35:992–997. doi: 10.1161/01.STR.0000119754.85848.0D. [DOI] [PubMed] [Google Scholar]
  • 9.Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006;354:2034–2045. doi: 10.1056/NEJMra052706. [DOI] [PubMed] [Google Scholar]
  • 10.Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A. 2000;97:10526–10531. doi: 10.1073/pnas.97.19.10526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Erbayraktar S, Grasso G, Sfacteria A, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A. 2003;100:6741–6746. doi: 10.1073/pnas.1031753100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Leist M, Ghezzi P, Grasso G, et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004;305:239–242. doi: 10.1126/science.1098313. [DOI] [PubMed] [Google Scholar]
  • 13.Wang L, Zhang Z, Wang Y, et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35:1732–1737. doi: 10.1161/01.STR.0000132196.49028.a4. [DOI] [PubMed] [Google Scholar]
  • 14.Fisher M, Meadows ME, Do T, et al. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1995;15:953–959. doi: 10.1038/jcbfm.1995.121. [DOI] [PubMed] [Google Scholar]
  • 15.Sugimori H, Speller H, Finklestein SP. Intravenous basic fibroblast growth factor produces a persistent reduction in infarct volume following permanent focal ischemia in rats. Neurosci Lett. 2001;300:13–16. doi: 10.1016/S0304-3940(01)01549-X. [DOI] [PubMed] [Google Scholar]
  • 16.Kawamata T, Alexis NE, Dietrich WD, Finklestein SP. Intracisternal basic fibroblast growth factor (bFGF) enhances behavioral recovery following focal cerebral infarction in the rat. J Cereb Blood Flow Metab. 1996;16:542–547. doi: 10.1097/00004647-199607000-00003. [DOI] [PubMed] [Google Scholar]
  • 17.Kawamata T, Dietrich WD, Schallert T, et al. Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc Natl Acad Sci U S A. 1997;94:8179–8184. doi: 10.1073/pnas.94.15.8179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Jiang N, Finklestein SP, Do T, Caday CG, Charette M, Chopp M. Delayed intravenous administration of basic fibroblast growth factor (bFGF) reduces infarct volume in a model of focal cerebral ischemia/reperfusion in the rat. J Neurol Sci. 1996;139:173–179. doi: 10.1016/0022-510X(96)00052-4. [DOI] [PubMed] [Google Scholar]
  • 19.Ren JM, Finklestein SP. Time window of infarct reduction by intravenous basic fibroblast growth factor in focal cerebral ischemia. Eur J Pharmacol. 1997;327:11–16. doi: 10.1016/S0014-2999(97)89672-0. [DOI] [PubMed] [Google Scholar]
  • 20.Berry D, Ren J, Kwan CP, Sietsma DK, Sasisekharan R, Finklestein SP. Dimeric fibroblast growth factor-2 enhances functional recovery after focal cerebral ischemia. Restor Neurol Neurosci. 2005;23:251–256. [PubMed] [Google Scholar]
  • 21.Bethel A, Kirsch JR, Koehler RC, Finklestein SP, Traystman RJ. Intravenous basic fibroblast growth factor decreases brain injury resulting from focal ischemia in cats. Stroke. 1997;28:609–615. doi: 10.1161/01.STR.28.3.609. [DOI] [PubMed] [Google Scholar]
  • 22.Li Q, Stephenson D. Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat. Exp Neurol. 2002;177:531–537. doi: 10.1006/exnr.2002.7994. [DOI] [PubMed] [Google Scholar]
  • 23.Watanabe T, Okuda Y, Nonoguchi N, et al. Postischemic intraventricular administration of FGF-2 expressing adenoviral vectors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2004;24:1205–1213. doi: 10.1097/01.WCB.0000136525.75839.41. [DOI] [PubMed] [Google Scholar]
  • 24.Baldauf K, Reymann KG. Influence of EGF/bFGF treatment on proliferation, early neurogenesis and infarct volume after transient focal ischemia. Brain Res. 2005;1056:158–167. doi: 10.1016/j.brainres.2005.07.035. [DOI] [PubMed] [Google Scholar]
  • 25.Schabitz WR, Kollmar R, Schwaninger M, et al. Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke. 2003;34:745–751. doi: 10.1161/01.STR.0000057814.70180.17. [DOI] [PubMed] [Google Scholar]
  • 26.Schneider A, Kruger C, Steigleder T, 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. doi: 10.1172/JCI23559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kawada H, Takizawa S, Takanashi T, et al. 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. doi: 10.1161/CIRCULATIONAHA.105.563668. [DOI] [PubMed] [Google Scholar]
  • 28.Jin K, Sun Y, Xie L, Childs J, Mao XO, Greenberg DA. Postischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 2004;24:399–408. doi: 10.1097/00004647-200404000-00005. [DOI] [PubMed] [Google Scholar]
  • 29.Sugiura S, Kitagawa K, Tanaka S, et al. Adenovirus-mediated gene transfer of heparin-binding epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke. 2005;36:859–864. doi: 10.1161/01.STR.0000158905.22871.95. [DOI] [PubMed] [Google Scholar]
  • 30.Guan J, Williams C, Gunning M, Mallard C, Gluckman P. The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats. J Cereb Blood Flow Metab. 1993;13:609–616. doi: 10.1038/jcbfm.1993.79. [DOI] [PubMed] [Google Scholar]
  • 31.Guan J, Miller OT, Waugh KM, McCarthy DC, Gluckman PD. Insulin-like growth factor-1 improves somatosensory function and reduces the extent of cortical infarction and ongoing neuronal loss after hypoxia-ischemia in rats. Neuroscience. 2001;105:299–306. doi: 10.1016/S0306-4522(01)00145-2. [DOI] [PubMed] [Google Scholar]
  • 32.Schabitz WR, Hoffmann TT, Heiland S, et al. Delayed neuroprotective effect of insulin-like growth factor-I after experimental transient focal cerebral ischemia monitored with MRI. Stroke. 2001;32:1226–1233. doi: 10.1161/01.STR.32.5.1226. [DOI] [PubMed] [Google Scholar]
  • 33.Zhao X, Liu SJ, Zhang J, Strong R, Aronowski J, Grotta JC. Combining insulin-like growth factor derivatives plus caffeinol produces robust neuroprotection after stroke in rats. Stroke. 2005;36:129–134. doi: 10.1161/01.STR.0000149624.87661.18. [DOI] [PubMed] [Google Scholar]
  • 34.Greenberg DA, Jin K. From angiogenesis to neuropathology. Nature. 2005;438:954–959. doi: 10.1038/nature04481. [DOI] [PubMed] [Google Scholar]
  • 35.Zhang ZG, Zhang L, Jiang Q, et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106:829–838. doi: 10.1172/JCI9369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111:1843–1851. doi: 10.1172/JCI17977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Thome RG, Frey WH. Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet. 2001;40:907–946. doi: 10.2165/00003088-200140120-00003. [DOI] [PubMed] [Google Scholar]
  • 38.Ilium L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci. 2000;11:1–18. doi: 10.1016/S0928-0987(00)00087-7. [DOI] [PubMed] [Google Scholar]
  • 39.Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci. 2002;5:514–516. doi: 10.1038/nn0602-849. [DOI] [PubMed] [Google Scholar]
  • 40.Jin K, Xie L, Childs J, et al. Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann Neurol. 2003;53:405–409. doi: 10.1002/ana.10506. [DOI] [PubMed] [Google Scholar]
  • 41.Yu YP, Xu QQ, Zhang Q, Zhang WP, Zhang LH, Wei EQ. Intranasal recombinant human erythropoietin protects rats against focal cerebral ischemia. Neurosci Lett. 2005;387:5–10. doi: 10.1016/j.neulet.2005.07.008. [DOI] [PubMed] [Google Scholar]
  • 42.Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey WH. Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci. 2001;187:91–97. doi: 10.1016/S0022-510X(01)00532-9. [DOI] [PubMed] [Google Scholar]
  • 43.Liu XF, Fawcett JR, Thorne RG, Frey WH. Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett. 2001;308:91–94. doi: 10.1016/S0304-3940(01)01982-6. [DOI] [PubMed] [Google Scholar]
  • 44.Zhao HM, Liu XF, Mao XW, Chen CF. Intranasal delivery of nerve growth factor to protect the central nervous system against acute cerebral infarction. Chin Med Sci J. 2004;19:257–261. [PubMed] [Google Scholar]
  • 45.Liu J, Solway K, Messing RO, Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci. 1998;18:7768–7778. doi: 10.1523/JNEUROSCI.18-19-07768.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Gu W, Brannstrom T, Wester P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab. 2000;20:1166–1173. doi: 10.1097/00004647-200008000-00002. [DOI] [PubMed] [Google Scholar]
  • 47.Jin K, Minami M, Lan JQ, et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA. 2001;98:4710–4715. doi: 10.1073/pnas.081011098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Zhang RL, Zhang ZG, Zhang L, Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience. 2001;105:33–41. doi: 10.1016/S0306-4522(01)00117-8. [DOI] [PubMed] [Google Scholar]
  • 49.Nakatomi H, Kuriu T, Okabe S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429–441. doi: 10.1016/S0092-8674(02)00862-0. [DOI] [PubMed] [Google Scholar]
  • 50.Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–970. doi: 10.1038/nm747. [DOI] [PubMed] [Google Scholar]
  • 51.Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol. 2002;52:802–813. doi: 10.1002/ana.10393. [DOI] [PubMed] [Google Scholar]
  • 52.Jin K, Sun Y, Xie L, et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci. 2003;24:171–189. doi: 10.1016/S1044-7431(03)00159-3. [DOI] [PubMed] [Google Scholar]
  • 53.Raber J, Fan Y, Matsumori Y, et al. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol. 2004;55:381–389. doi: 10.1002/ana.10853. [DOI] [PubMed] [Google Scholar]
  • 54.Teramoto T, Qiu J, Plumier JC, Moskowitz MA. EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. J Clin Invest. 2003;111:1125–1132. doi: 10.1172/JCI17170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Tsai PT, Ohab JJ, Kertesz N, et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci. 2006;26:1269–1274. doi: 10.1523/JNEUROSCI.4480-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Wada K, Sugimori H, Bhide PG, Moskowitz MA, Finklestein SP. Effect of basic fibroblast growth factor treatment on brain progenitor cells after permanent focal ischemia in rats. Stroke. 2003;34:2722–2728. doi: 10.1161/01.STR.0000094421.61917.71. [DOI] [PubMed] [Google Scholar]
  • 57.Tureyen K, Vemuganti R, Bowen KK, Sailor KA, Dempsey RJ. EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery. 2005;57:1254–63. doi: 10.1227/01.NEU.0000186040.96929.8A. [DOI] [PubMed] [Google Scholar]
  • 58.Jin K, Mao XO, Sun Y, Xie L, Greenberg DA. Stem cell factor stimulates neurogenesis in vitro and in vivo. J Clin Invest. 2002;110:311–319. doi: 10.1172/JCI15251. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from NeuroRx are provided here courtesy of Am. Soc. for Experimental NeuroTherapeutics

RESOURCES