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Neurological Sciences

, Volume 32, Issue 3, pp 433–441 | Cite as

Therapeutic time window for the neuroprotective effects of NGF when administered after focal cerebral ischemia

  • Ji-Ping Yang
  • Huai-Jun LiuEmail author
  • Hua Yang
  • Ping-Yong Feng
Original Article

Abstract

In the present study, we evaluated the neuroprotection time window for nerve growth factor (NGF) after ischemia/reperfusion brain injury in rabbits as related to this anti-apoptosis mechanism. Male New Zealand rabbits were subjected to 2 h of middle cerebral artery occlusion (MCAO), followed by 70 h of reperfusion. NGF was administered after injury to evaluate the time window. Neurological deficits, infarct volume, neural cell apoptosis and expressions of caspase-3 and Bcl-2 were measured. Compared to saline-treated control, NGF treatment at 2, 3 and 5 h after MCAO significantly reduced infarct volume, neural cell apoptosis and expression of caspase-3 (P < 0.01), up-regulated the expression of Bcl-2 and improved functional recovery (P < 0.01). However, treatment at latter time points did not produce significant neuroprotection. Neuroprotection treatment with NGF provides an extended time window of up to 5 h after ischemia/reperfusion brain injury, in part by attenuating the apoptosis.

Keywords

Focal cerebral ischemia Nerve growth factor Neuroprotection Time window Bcl-2 Apoptosis 

Notes

Acknowledgments

This study was supported by the China Ministry of Health Science Foundation (#200310, Dr. Liu), Hebei Natural Science Foundation (#C2010000557, Dr. Yang), Hebei Key Program of Medical Research (#20090101, Dr. Yang) and China Postdoctor Science Foundation (#20070411051, Dr. Yang).

References

  1. 1.
    Chopp M, Zhang ZG, Jiang Q (2007) Neurogenesis, angiogenesis, and MRI indices of functional recovery from stroke. Stroke 38(2 Suppl):827–831PubMedCrossRefGoogle Scholar
  2. 2.
    Moonis M, Fisher M (2003) Antiplatelet treatment for secondary prevention of acute ischemic stroke and transient ischemic attacks: mechanisms, choices and possible emerging patterns of use. Expert Rev Cardiovasc Ther 1:611–615PubMedCrossRefGoogle Scholar
  3. 3.
    Fisher M, for the Stroke Therapy Academic Industry Roundtable (2003) Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable. Stroke 34:1539–1546Google Scholar
  4. 4.
    Williams AJ, Berti R, Dave J et al (2004) Delayed treatment of ischemia/reperfusion brain injury extended therapeutic window with the proteosome inhibitor MLN519. Stroke 35:1186–1191PubMedCrossRefGoogle Scholar
  5. 5.
    Stroke Therapy Academic Industry Roundtable (STAIR) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30: 2752–2758Google Scholar
  6. 6.
    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162PubMedCrossRefGoogle Scholar
  7. 7.
    Mattson MP, Lovell MA, Furukawa K et al (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of intracellular Ca2+ concentration, and neurotoxicity and increase antioxidant enzyme activities in hippocampal neurons. J Neurochem 65:1740–1751PubMedCrossRefGoogle Scholar
  8. 8.
    Shimohama S, Ogawa N, Tamura Y et al (1993) Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons. Brain Res 632:296–302PubMedCrossRefGoogle Scholar
  9. 9.
    Batistatou A, Greene LA (1991) Aurintricarboxylic acid rescues PC12 cells and sympathetic neurons from cell death caused by nerve growth factor deprivation: correlation with suppression of endonuclease activity. J Cell Biol 115:461–471PubMedCrossRefGoogle Scholar
  10. 10.
    Inagaki N, Thoenen H, Lindholm D (1995) TrkA tyrosine residues involved in NGF-induced neurite outgrowth of PC12 cells. Eur J Neurosci 7:1125–1133PubMedCrossRefGoogle Scholar
  11. 11.
    Segal RA, Greenberg ME (1996) Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 19:463–489PubMedCrossRefGoogle Scholar
  12. 12.
    Cheng B, Mattson MP (1991) NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron 7:1031–1041PubMedCrossRefGoogle Scholar
  13. 13.
    Semkova I, Schilling M, Henrich-Noack P et al (1996) Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF. Brain Res 717:44–54PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang Y, Tatsuno T, Carney JM et al (1993) Basic FGF, NGF, and IGFs protect hippocampal and cortical neurons against iron-induced degeneration. J Cereb Blood Flow Metab 13:378–388PubMedCrossRefGoogle Scholar
  15. 15.
    Shigeno T, Mima T, Takakura K et al (1991) Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci 11:2914–2919PubMedGoogle Scholar
  16. 16.
    Pechan PA, Yoshida T, Panahian N et al (1995) Genetically modified fibroblasts producing NGF protect hippocampal neurons after ischemia in the rat. Neuroreport 6:669–672PubMedCrossRefGoogle Scholar
  17. 17.
    Semkova I, Schilling M, Henrich-Noack P et al (1996) Clenbuterol protects mouse cerebral cortex and rat hippocampus from ischemic damage and attenuates glutamate neurotoxicity in cultured hippocampal neurons by induction of NGF. Brain Res 717:44–54PubMedCrossRefGoogle Scholar
  18. 18.
    Tabakman R, Jiang H, Shahar I et al (2005) Neuroprotection by NGF in the PC12 in vitro OGD model. Ann NY Acad Sci 1053:84–96PubMedCrossRefGoogle Scholar
  19. 19.
    Shigeno T, Mima T, Takakura K et al (1991) Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci 11:2914–2919PubMedGoogle Scholar
  20. 20.
    Pechan PA, Yoshida T, Panahian N et al (1995) Genetically modified fibroblasts producing NGF protect hippocampal neurons after ischemia in the rat. Neuroreport 6:669–672PubMedCrossRefGoogle Scholar
  21. 21.
    Guégan C, Onténiente B, Makiura Y et al (1998) Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia. Brain Res Mol Brain Res 55:133–140PubMedCrossRefGoogle Scholar
  22. 22.
    Yang JP, Liu XF, Liu HJ et al (2008) Extracellular signal-regulated kinase involved in NGF/VEGF-induced neuroprotective effect. Neurosci Lett 434:212–217PubMedCrossRefGoogle Scholar
  23. 23.
    Yang JP, Liu HJ, Liu RC (2009) A modified rabbit model of stroke: evaluation using clinical MRI scanner. Neurol Res 31:1092–1096PubMedCrossRefGoogle Scholar
  24. 24.
    Manabat C, Han BH, Wendland M et al (2003) Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain. Stroke 34:207–213PubMedCrossRefGoogle Scholar
  25. 25.
    Purdy PD, Devous MD Sr, Batijer HH et al (1989) Microfibrillar collagen model of canine cerebral infarction. Stroke 20:1361–1367PubMedGoogle Scholar
  26. 26.
    Schäbitz WR, Hoffmann TT, Heiland S et al (2001) Delayed neuroprotective effect of insulin-like growth factor-I after experimental transient focal cerebral ischemia monitored with MRI. Stroke 32:1226–1233PubMedGoogle Scholar
  27. 27.
    Linnik MD, Miller JA, Sprinkle-Cavallo J et al (1995) Apoptosis DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. Mol Brain Res 32:116–124PubMedCrossRefGoogle Scholar
  28. 28.
    Butcher K, Emery D (2010) Acute stroke imaging. Part II: the ischemic penumbra. Can J Neurol Sci 37:17–27PubMedGoogle Scholar
  29. 29.
    Schaller B, Graf R (2004) Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab 24:351–371PubMedCrossRefGoogle Scholar
  30. 30.
    Butte MJ, Hwang PK, Mobley WC et al (1998) Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Biochemistry 37:16846–16852PubMedCrossRefGoogle Scholar
  31. 31.
    Ibáñez CF (1994) Structure–function relationships in the neurotrophin family. J Neurobiol 25:1349–1361PubMedCrossRefGoogle Scholar
  32. 32.
    Robinson RC, Radziejewski C, Spraggon G et al (1999) The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci 8:2589–2597PubMedCrossRefGoogle Scholar
  33. 33.
    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736PubMedCrossRefGoogle Scholar
  34. 34.
    Schinder AF, Poo M (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci 23:639–645PubMedCrossRefGoogle Scholar
  35. 35.
    Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog Brain Res 128:183–191PubMedCrossRefGoogle Scholar
  36. 36.
    Tabakman R, Lecht S, Sephanova S et al (2004) Interactions between the cells of the immune and nervous system: neurotrophins as neuroprotection mediators in CNS injury. Prog Brain Res 146:387–401PubMedGoogle Scholar
  37. 37.
    Barbacid M (1994) The Trk family of neurotrophin receptors. J Neurobiol 25:1386–1403PubMedCrossRefGoogle Scholar
  38. 38.
    Kaplan DR, Miller FD (1997) Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 9:213–221PubMedCrossRefGoogle Scholar
  39. 39.
    Gall CM, Isackson PJ (1989) Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 245:758–761PubMedCrossRefGoogle Scholar
  40. 40.
    Zafra F, Castrén E, Thoenen H (1991) Interplay between glutamate and gamma-aminobutyric acid transmitter systems in the physiological regulation of brain-derived neurotrophic factor and nerve growth factor synthesis in hippocampal neurons. Proc Natl Acad Sci USA 88:10037–10041PubMedCrossRefGoogle Scholar
  41. 41.
    Batchelor PE, Armstrong DM, Blaker SN et al (1989) Nerve growth factor receptor and choline acetyltransferase colocalization in neurons within the rat forebrain. J Comp Neurol 284:187–204PubMedCrossRefGoogle Scholar
  42. 42.
    Hagg T, Manthorpe M, Vahlsing HL et al (1988) Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage. Exp Neuro 101:303–312CrossRefGoogle Scholar
  43. 43.
    Hagg T, Hagg F, Vahlsing HL et al (1989) Nerve growth factor effects on cholinergic neurons of neostriatum and nucleus accumbens in the adult rat. Neuroscience 30:95–103PubMedCrossRefGoogle Scholar
  44. 44.
    Hefti F, Hartikka J, Salvatierra A et al (1986) Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain. Neurosci Lett 69:37–41PubMedCrossRefGoogle Scholar
  45. 45.
    Montero CN, Hefti F (1988) Rescue of lesioned septal cholinergic neurons by nerve growth factor: Specificity and requirement for chronic treatment. J Neurosci 8:2986–2999PubMedGoogle Scholar
  46. 46.
    Vantini G, Schiavo N, Martino AD et al (1989) Evidence for a physiological role of nerve growth factor in the central nervous system of neonatal rats. Neuron 3:267–273PubMedCrossRefGoogle Scholar
  47. 47.
    Tanaka K, Tsukahara T, Kaku Y et al (1994) Effect of nerve growth factor on delayed neuronal death and microtubule-associated protein 2 after transient cerebral ischaemia in the rat. J Clin Neurosci 1:125–130PubMedCrossRefGoogle Scholar
  48. 48.
    Dumont DJ, Fong GH, Puri MC et al (1995) Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn 203:80–92PubMedCrossRefGoogle Scholar
  49. 49.
    Li DQ, Bao YM, Zhao JJ et al (2004) Neuroprotective properties of catalpol in transient global cerebral ischemia in gerbils: dose-response, therapeutic time-window and long-term efficacy. Brain Res 1029:179–185PubMedCrossRefGoogle Scholar
  50. 50.
    Wasserman JK, Schlichter LC (2007) Neuron death and inflammation in a rat model of intracerebral hemorrhage: effects of delayed minocycline treatment. Brain Res 1136:208–218PubMedCrossRefGoogle Scholar
  51. 51.
    Aronowski J, Strong R, Grotta JC (1997) Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats. J Cereb Blood Flow Metab 17:1048–1056PubMedCrossRefGoogle Scholar
  52. 52.
    Muller TB, Haraldseth O, Jones RA et al (1995) Combined perfusion and diffusion-weighted magnetic resonance imaging in a rat model of reversible middle cerebral artery occlusion. Stroke 26:451–457PubMedGoogle Scholar
  53. 53.
    Maier CM, Sun GH, Kunis D et al (2001) Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 94:90–96PubMedCrossRefGoogle Scholar
  54. 54.
    Karibe H, Zarow GJ, Graham SH et al (1994) Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, blood–brain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats. J Cereb Blood Flow Metab 14:620–627PubMedCrossRefGoogle Scholar
  55. 55.
    Jean WC, Spellman SR, Nussbaum ES et al (1998) Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery 43:1382–1396PubMedGoogle Scholar
  56. 56.
    Saragovi HU, Gehring K (2000) Development of pharmacological agents for targeting neurotrophins and their receptors. Trends Pharmacol Sci 21:93–98PubMedCrossRefGoogle Scholar
  57. 57.
    Thorne RG, Frey WH II (2001) Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet 40:907–946PubMedCrossRefGoogle Scholar
  58. 58.
    Krüttgen A, Schneider I, Weis J (2006) The dark side of the NGF family: neurotrophins in neoplasias. Brain Pathol 16:304–310PubMedCrossRefGoogle Scholar
  59. 59.
    Frey WH II, Liu J, Chen X et al (1997) Delivery of 125I-NGF to the brain via the olfactory route. Drug Deliv 4:87–92CrossRefGoogle Scholar
  60. 60.
    Zhao HM, Liu XF, Mao XW et al (2004) Intranasal delivery of nerve growth factor to protect the central nervous system against acute cerebral infarction. Chin Med Sci J 19:257–261PubMedGoogle Scholar
  61. 61.
    Nitatori T, Sato N, Waguri S et al (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15:1001–1011PubMedGoogle Scholar
  62. 62.
    Li Y, Sharov VG, Jiang N et al (1995) Ultrastructural and light microscopic evidence of apoptosis after middle cerebral artery occlusion in the rat. Am J Pathol 146:1045–1051PubMedGoogle Scholar
  63. 63.
    Chen J, Nagayama T, Jin K et al (1998) Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18:4914–4928PubMedGoogle Scholar
  64. 64.
    Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399:A7–A14PubMedGoogle Scholar
  65. 65.
    Schulz JB, Weller M, Moskowitz MA (1999) Caspases as treatment targets in stroke and neurodegenerative diseases. Ann Neurol 45:421–429PubMedCrossRefGoogle Scholar
  66. 66.
    Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487PubMedCrossRefGoogle Scholar
  67. 67.
    Yang J, Liu X, Bhalla K et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132PubMedCrossRefGoogle Scholar
  68. 68.
    Lan X, Qu H, Yao W et al (2008) Granulocyte-colony stimulating factor inhibits neuronal apoptosis in a rat model of diabetic cerebral ischemia. Tohoku J Exp Med 216:117–126PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ji-Ping Yang
    • 1
  • Huai-Jun Liu
    • 1
    Email author
  • Hua Yang
    • 1
  • Ping-Yong Feng
    • 1
  1. 1.Department of Medical ImagingThe Second Hospital of Hebei Medical UniversityShijiazhuangChina

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