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Neurotrophic factors in neurodegenerative disorders: Model of parkinson’s disease

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Abstract

Neurotrophic factors are compounds that enhance neuronal survival and differentiation. Most of these compounds exert their pharmacological actions on selective types of neurons, and therefore, are considered promising new therapeutic agents for the treatment of different neurodegenerative disorders characterized by selective degeneration of certain neuronal groups. Those compounds have been used in humans for several neurological disorders including amyotrophic lateral sclerosis — ciliary derived neurotrophic factor (CNTF) and brain derived neurotrophic factor (BDNF), Alzheimer’s disease and peripheral neuropathy — nerve growth factor (NGF) and Parkinson’s disease (PD) — glial derived neurotrophic factor (GDNF).

In spite of well founded clinical experiments by previous experimental work in animal models some of these trials have been negative. For instance, animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxinsin vitro. These compounds prevent or recover the damage to dopamine neurons of rodents and primates produced by chemical or mechanical acute lesions including 6-OHDA, MPTP, methamphetamine and axotomy.

The differences between the promising results obtained in experimental models and the lack of clinical results or excessive toxicity found in humans could be attributed to the following reasons: (a) Lack of relevance between the pathogenesis of the experimental lesion and the corresponding neurodegenerative disorder. (b) Poor correlation between results obtained in acute, self-limited, selective deficit produced to experimental animals and those available in more complex, chronic and progressive disorders involving patients. (c) Inadequate delivery of the active product to the target area in the human brain. (d) Poor information from acute experiments in animals which does not predict long-term effects of chronic infusion in humans. Further experimental work, therefore, is needed to transfer these neurotrophic factors to the clinic.

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References

  • Abraham, I., Sampson, K.E., Powers, E.A., Mayo, J.K., Ruff, V.A. and Leach, K.L. (1991) Increased PKA and PKC activities accompany neuronal differentiation of NT2/D1 cells.J. Neurosci. Res. 28, 29–39.

    Article  PubMed  CAS  Google Scholar 

  • Adamson, D.E. and Meek, J. (1984) The ontogeny of epidermal growth factor receptor during mouse development.Dev. Biol. 103, 62–70.

    Article  PubMed  CAS  Google Scholar 

  • Albert, K.A., Helmer-Matyjek, E., Nairn, A.C., Muller, T.H., Haycock, J.W., Greene, L.A., Goldsstein, M. and Greengard, P. (1984) Calcium/phospholipid-dependent protein kinase (PKC) phosphorylates and activates tyrosine hydroxylase.Proc. Natl. Acad. Sci. 81, 713–7717.

    Article  Google Scholar 

  • Alexi, T. and Hefti, F. (1993) Trophic actions of transforming growth factor alpha on mesencephalic dopaminergic neurons developing in culture.Neuroscience 55, 903–910.

    Article  PubMed  CAS  Google Scholar 

  • Alexi, T., Venero, J.L. and Hefti, F. (1997) Protective effects of neurotrophin-4/5 and transforming growth factor-alpha on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid.Neuroscience 78, 73–86.

    Article  PubMed  CAS  Google Scholar 

  • Altar, CA., Boylan, C.B., Fritsche, M., Jones, B.E., Jackson, C, Wiegand, S.J., Lindsay, R.M. and Hyman, C. (1994) Efficacy of brain derived neurotrophic factor and neurotrophin 3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions.J. Neurochem. 63, 1021–1032.

    Article  PubMed  CAS  Google Scholar 

  • Anderson, K.J.D., Dam, D., Lee, S. and Cotman, C.W. (1988) Basic fibroblast growth factor prevents death of lesioned cholinergic neuronsin vivo.Nature 332, 360–362.

    Article  PubMed  CAS  Google Scholar 

  • Arakawa, Y, Sendtner, M. and Thoenen, H. (1990) Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines.J. Neurosci. 10, 3507–3515.

    PubMed  CAS  Google Scholar 

  • Araujo, D.M. and Hilt, D.C. (1997) Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington’s disease.Neuroscience 81, 1099–1110.

    Article  PubMed  CAS  Google Scholar 

  • Asai, T., Wanaka, A., Kato, H., Masana, Y., Seo, M. and Tohyama, M. (1993) Differential expression of two members of FGF receptor gene family, FGFR-1 and FGFR-2 mRNA, in the adult rat central nervous system.Mol. Brain Res. 17, 174–178.

    Article  PubMed  CAS  Google Scholar 

  • Barde, Y.A., Edgar, D. and Thoenen, H. (1982) Purification of a new neurotrophic factor from mammalian brain.EMBO J. 1, 549–553.

    PubMed  CAS  Google Scholar 

  • Baskin, D.G., Wilcox, B.J., Figlewicz, D.P. and Dorsa, D.M. (1988) Insulin and insulin-like growth factors in the CNS.TINS 11, 107–111.

    PubMed  CAS  Google Scholar 

  • Bazan, E., Lopez-Toledano, M.A., Redondo, C., Reimers, D., Paino, C.L., Herranz, A.S. and Mena, M.A. (1999). Basic Fibroblast growth factor and protein kinase A activators cooperate to induce the expression of tyrosine hydroxylase in striatal neural stem cells.Soc. Neurosci. 25, (Abstract) 1539.

    Google Scholar 

  • Bean, A.J., Eide, R., Cao, Y, Oellig, C, Tamminga, C, Goldstein, M, Pettersson, R.F. and Hokfelt, T. (1991) Expression of acidic and basic fibroblast growth factors in the sustantia nigra of rat, monkey and human.Proc. Natl. Acad. Sci. USA 88, 10237–10241.

    Article  PubMed  CAS  Google Scholar 

  • Beck, K.D., Knusel, B. and Hefti, F. (1991) The nature of trophic action of brain derived neurotrophic factor, des (1-3)- insulin-like growth factor-1 and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture.Neuroscience 52, 855–866.

    Article  Google Scholar 

  • Beck, K.D. (1994) Functions of brain-derived neurotrophic factor, insulin-like growth factor-I and basic fibroblast growth factor in the development and maintenance of dopaminergic neurons.Prog. Neurobiol. 44, 497–516.

    Article  PubMed  CAS  Google Scholar 

  • Beck, K.D., Valverde, J., Alexi, T., Poulsen, K., Moffat, B., Vandlen, R.A. and Hefti, F. (1995) Mesencephalic dopaminergic neurons protected by GDNF from axotomy induced degeneration in the adult brain.Nature 373, 339–341.

    Article  PubMed  CAS  Google Scholar 

  • Björklund, A. (1994) Better cells for brain repair.Nature 362, 414–415.

    Article  Google Scholar 

  • Blottner, D., Westermann, R., Grothe, C, Bohlen, P. and Unsicker, K. (1989) Basic fibroblast growth factor in the adrenal gland: possible trophic role for preganglionic neuronsin vivo.Eur. J. Neurosci. 1, 471–478.

    Article  PubMed  Google Scholar 

  • Blum, M. and Weicker, C.S. (1995) GDNF mRNA expression in normal post-natal development, aging and the weaver mutant mice.Neurobiol. Aging 16, 925–929.

    Article  PubMed  CAS  Google Scholar 

  • Boonstra, J., Mummery, C.L., Feyen, A., de Hoog, W.J., van der Saag, P.T. and de Laat, S.W. (1987) Epidermal growth factor receptor expression during morphological differentiation of pheochromocytoma cells, induced by nerve growth factor or dibutyryl cyclic AMP.J. Cell Physiol. 131, 409–417.

    Article  PubMed  CAS  Google Scholar 

  • Bowenkamp, K.E., Hoffman, A.F., Gerhardt, G.A., Hoffer, B.J. and Lin, L.F. (1995) Glial cell line derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons.J. Conip. Neurol. 355, 479–489.

    Article  CAS  Google Scholar 

  • Carpenter, G. (1985) Epidermal growth factor. Biology and receptor metabolism.J. Cell Sci. 3(Suppl.), 1–9.

    CAS  Google Scholar 

  • Casarejos, M.J. (1995) Factores de diferenciación para neuronas dopaminérgicas. Tesis doctoral, Universidad Autonoma de Madrid, Facultad de Ciencias, Madrid.

  • Chen, X.L., Roisen, F.J. and Gupta, M. (1996) The effect of priorin vitro exposure of donor cells to trophic factors in neurotransplantation.Exp. Neurol. 138, 64–72.

    Article  PubMed  CAS  Google Scholar 

  • Cintra, A., Cao, Y., Oellig, C, Tinner, B., Bortolotti, E, Goldstein, M., Pettersson, R.F. and Fuxe, K. (1991) Basic FGF is present in dopaminergic neurons of the ventral midbrain of the rat.NeuroReport 2, 597–600.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, S. (1962) Isolation of a mouse submaxilary gland protein accelerating incisor eruption and eyelid opening in the new born animal.J. Biol. Chem. 237, 1555–1562.

    PubMed  CAS  Google Scholar 

  • Cohen, S. and Carpenter, G. (1975) Human epidermal growth factor: Isolation and chemical and biological properties.Proc. Natl. Acad. Sci. USA 72, 1317–1321.

    Article  PubMed  CAS  Google Scholar 

  • Connor, B. and Dragunow, M. (1998) The role of neural growth factors in degenerative disorders of the human brain.Brain Res. Rew. 27, 1–39.

    CAS  Google Scholar 

  • Cowan, W.M. (1973) Neuronal death as a regulative mechanism in the control of cell number in the nervous system. In: Rockstein, M. (Ed)Development and Aging in the Nervous System. Academic Press, New York, pp. 19–41.

    Google Scholar 

  • Date, I., Notter, M.F.D., Feiten, S.Y. and Feiten, D.L. (1990) MPTP-treated young mice but not aging mice show partial recovery of the nigrostriatal dopaminergic system by stereotaxic injection of acidic fibroblast growth factor (aFGF).Brain Res. 526, 156–160.

    Article  PubMed  CAS  Google Scholar 

  • Dean, B. and Copolov, D.L. (1990) Phorbol esters increase3H- dopamine uptake by human platelets.Platelets 1, 135–137.

    Article  CAS  Google Scholar 

  • De Yébenes, J.G., Mena, M.A., Dwork, A., Latov, N., Fahn, S. and Herbert, J. (1988) Transplantation of human neuroblastoma cells in 6-OH-DA lesioned rats.Neurology 38, (Abstract) 129.

    Article  Google Scholar 

  • De Yébenes, J.G., Sánchez-Pernaute, R., Garrido, J.M., Rabano, A., Rojo, A., Mena, M.A., Garcia, P.G., Jorge, P., Leenders, K., Gunther, I., Psylla, M. and Vontobel, P. (1996) Effects of neurotrophic factors in MPTP lesioned monkeys.Neurology 46, (Abstract) 443.

    Google Scholar 

  • De Yébenes, J.G., Sánchez-Pernaute, R., Garrido, J.M., Rabano, A., Rojo, A., Mena, M.A., Garcia, P.G., Jorge, P., Leenders, K., Günther, I., Psylla, M. and Vontobel, P. (1998) Effects of chronic intrastriatal infusion of fibroblast growth factors in monkeys with unilateral nigrostriatal dopamine lesions.Parkinsonims and Related Disorders 4, 147–158.

    Article  Google Scholar 

  • Drago, J., Murphy, M., Carroll, S.M., Harvey, R.P. and Bartlett, P.F. (1991) Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor.Proc. Natl. Acad. Sci. USA 88, 2199–2203.

    Article  PubMed  CAS  Google Scholar 

  • Emerich, D.F., Winn, S.R., Hantraye, P.M., Chen, E.Y, Chu, Y, McDermont, P., Baetge, E.E. and Kordower, J.H. (1997) Protective effect of encapsulated cells producing neurotrophic factor CNTF in a model of Huntington’s disease.Nature 386, 395–399.

    Article  PubMed  CAS  Google Scholar 

  • Engele, J. and Bohn, M.C. (1991) The neurotrophic effects of fibroblast growth factors on dopaminergic neuronsin vitro are mediated by mesencephalic glia.J. Neurosci. 11, 3070–3078.

    PubMed  CAS  Google Scholar 

  • Fadda, E., Negro, A., Facci, L. and Skaper, S.D.(1993) Ganglioside GM1 cooperates with brain-derived neurotrophic factor to protect dopaminergic neurons from 6-hydroxydopamine-induced degeneration.Neurosci. Lett. 159, 147–150.

    Article  PubMed  CAS  Google Scholar 

  • Fan, D., Ogawa, M., Ikeguchi, K., Fujimoto, K., Urabe, M., Kume, A., Nishizawa, M. and Matsushita, N. (1998) Prevention of dopaminergic neuron death by adeno-associated virus vector-mediated GDNF gene transfer in rat mesencephalic cellsin vitro. Neurosci. Lett. 248, 61–64.

    Article  CAS  Google Scholar 

  • Fernandez, A.M., De la Vega, A.G. and Torres-Aleman, I. (1998) Insulin-like growth factor I restores motor ccordination in a rat model of cerebellar ataxia.Proc. Natl. Acad. Sci. USA 95, 1253–1258.

    Article  PubMed  CAS  Google Scholar 

  • Ferrari, G., Minozzi, M.C, Toffano, G., Leon, A. and Skaper, S.D. (1989) Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons in culture.Dev. Biol. 133, 140–147.

    Article  PubMed  CAS  Google Scholar 

  • Ferrari, G., Toffano, G. and Skaper, S.D. (1991) Epidermal growth factor exerts neuronotrophic effects on dopaminergic and GABAergic neurons: comparison with basic fibroblast growth factor.J. Neurosci. Res. 30, 493–497.

    Article  PubMed  CAS  Google Scholar 

  • Fisher, L.J., Jinnah, H.A., Kale, L.C., Higgins, G.A. and Gage, F.H. (1991) Primary fibroblasts that produce L-DOPA: long term survival and behavioral effects when implanted into rats with 6-OHDA lesions.Neuron 6, 371–380.

    Article  PubMed  CAS  Google Scholar 

  • Flanders, K.C., Ren, R.F. and Lippa, CF. (1998) Transforming growth factor βs in neurodegenerative disease.Progr. Neurobiol. 54, 71–85.

    Article  CAS  Google Scholar 

  • Friden, P.M., Walus, L.R., Watson, P., Doctrow, S.R., Kozarich, J.W., Backman, C, Bergman, H., Hoffer, B., Bloom, F. and Granholm, A.C. (1993) Blood-brain barrier penetration andin vivo activity of an NGF conjugate.Science 259, 373–377.

    Article  PubMed  CAS  Google Scholar 

  • Frim, D.M., Uhler, T.A., Galpern, W.R., Beal, M.F., Breakefield, X.O. and Isacson, O. (1994) Implanted fibro- blasts genetically engineered to produce brain-derived neurotrophic factor prevent l-methyl-4-phenyl pyridinium toxicity to dopaminergic neurons in the rat.Proc. Natl. Acad. Sci. USA 91, 5104–5108.

    Article  PubMed  CAS  Google Scholar 

  • Gage, F.H., Kawaja, M.D. and Fisher, L. (1991) Genetically modified cells: applications for intracerebral grafting.TINS 14, 328–333.

    PubMed  CAS  Google Scholar 

  • Gash, D.M., Zhang, Z., Ovadia, A., Cass, W.A., Yi, A., Simmerman, L., Russell, D., Martin, D., Lapchak, P.A., Collins, F., Hoffer, B.J. and Gerhardt, G.A. (1996) Functional recovery in parkinsonian monkeys treated with GDNF.Nature 380, 252–255.

    Article  PubMed  CAS  Google Scholar 

  • Gash, D.M., Zhang, Z. and Gerhardt, G. (1998) Neuroprotective and neurorestorative properties of GDNF.Ann. Neurol. 44, 121–125.

    Google Scholar 

  • Gerhardt, G.A., Cass, W.A., Huetl, P., Brock, S., Zhang, Z. and Gash, D.M. (1999) GDNF improves dopamine function in the substantia nigra but not the putamen of unilateral MPTP-lesioned rhesus monkeys.Brain Res. 817, 163–171.

    Article  PubMed  CAS  Google Scholar 

  • Greene, L.A. and McGuire, J.C. (1978) Induction of ornithine decarboxylase by nerve growth factor dissociated from effects on survival and neurite outgrowth.Nature 276, 191–194.

    Article  PubMed  CAS  Google Scholar 

  • Greene, L.A. and Rein, G. (1977) Synthesis, storage and release of acetylcholine by a noradrenergic pheochromocytoma cell line.Nature 268, 349–351.

    Article  PubMed  CAS  Google Scholar 

  • Gregory, H. (1985)In vivo aspects of urogastrone-epidermal growth factor.J. Cell Sci. 3, 11–17.

    CAS  Google Scholar 

  • Gunning, P.W., Letourneau, P.C., Landreth, G.E., Shooter, E.M. (1981) The actions of nerve growth factors and dibutiryl adenosisne cyclic 3′-5′-monophosphate on rat pheochromocytoma reveals distinct stages in the mechanisms underlying neurite outgrowth.J. Neurosci,1, 1085–1095.

    PubMed  CAS  Google Scholar 

  • Hadjiconstantinou, M., Fitkin, J.G., Dalia, A. and Neff, N.H. (1991) Epidermal growth factor enhances striatal dopaminergic parameters in the l-methyl-4-phenyl-l,2,3,6,-tetra-hydropyridine treated mouse.J. Neurochem. 57, 479–482.

    Article  PubMed  CAS  Google Scholar 

  • Hagg, T. and Varon, S. (1993) Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neuronsin vivo.Proc. Natl. Acad. Sci. USA 90, 6315- 6319.

    Article  PubMed  CAS  Google Scholar 

  • Hagg, T. (1998) Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostriatal neuronsin vivo.Exp. Neurol. 149, 183–192.

    Article  PubMed  CAS  Google Scholar 

  • Hamburger, V. (1934) The effects of wing bud extirpation on the development of the central nervous system in chick embryos.J. Exp. Zool. 68, 449–494.

    Article  Google Scholar 

  • Hamburger, V. and Openheim, R.N. (1982) Naturally occurring neuronal death in vertebrates.Neurosci. Comm. 1, 39–55.

    Google Scholar 

  • Hefti, F., Hartikka, J. and Krusel, B. (1989) Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases.Neurobiol. Aging 10, 515–533.

    Article  PubMed  CAS  Google Scholar 

  • Heuckeroth, R.O., Enomoto, H., Grider, J.R., Golden, J.P., Hanke, J.A., Jjackman, A., Molliver, D.C., Bardett, M.E., Snider, W.D., Johnson, E.M. and Milbrandt, J. (1999) Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons.Neuron 22, 253–263.

    Article  PubMed  CAS  Google Scholar 

  • Hiramatsu, M., Kashimata, M., Sato, A., Murayama, M. and Minami, N. (1988) Influence of age on epidermal growth factor receptor level in the rat brain.Experientia 44, 23–25.

    Article  PubMed  CAS  Google Scholar 

  • Ho, A. and Blum, M. (1998) Induction of interleukin-1 associated with compensatory dopaminergic sprouting in the denervate striatum of young mice: model of aging and neurodegenerative disease.J. Neurosci. 18, 5614–5629.

    PubMed  CAS  Google Scholar 

  • Hofer, M.M. and Barde, Y.A. (1988) Brain-derived neurotrophic factor prevents neuronal detahin vivo.Nature 331, 261–262.

    Article  PubMed  CAS  Google Scholar 

  • Hoffer, B.J., Hoffman, A., Bowenkamp, K., Huetttl, P., Hudson, J., Martin, D., Lin, L.F. and Gerhardt, G.A. (1994) Glial cell line derived neurotrophic factor reverses toxin induced injury to midbrain dopaminergic neuronsin vivo.Neurosci. Lett. 182, 107–111.

    Article  PubMed  CAS  Google Scholar 

  • Hoffman, D., Brakefield, X.O., Short, M.P. and Aebischer, P. (1993) Transplantation of a polymer encapsulated cell line genetically engineered to release NGF.Exp. Neurol. 122, 100–106.

    Article  PubMed  CAS  Google Scholar 

  • Hohn, A., Leibrock, J., Bailey, K. and Barde, Y.A. (1990) Identification and characterization of a novel member of the nerve growth factor/brain derived growth factor family.Nature 334, 339–341.

    Article  Google Scholar 

  • Horellou, P., Brundin, P., Kalén, P., Mallet, J. and Bjorklund, A. (1990)In vivo release of DOPA and dopamine from genetically engineered cells grafted to the denervated rat striatum.Neuron 5, 393–402.

    Article  PubMed  CAS  Google Scholar 

  • Hudson, J., Granholm, A.C., Gerhardt, G.A., Henry, M.A., Hoffman, A., Biddle, P., Leela, N.S., Mackerlova, L., Lile, J.D. and Collins, F. (1995) Glial cell line derived neurotrophic factor augments midbrain dopaminergic circuitsin vivo.Brain Res. Bull 36, 425–432.

    Article  PubMed  CAS  Google Scholar 

  • Hou, J.G., Lin, L.F. and Mytilineou, C. (1996) Glial cell line derived neurotrophic factor exerts neurotrophic effects on dopaminergic neuronsin vitro and promotes their survival and regrowth after damage by l-methyl-4-phenylpyridi- nium.J. Neurochem. 66, 74–82.

    Article  PubMed  CAS  Google Scholar 

  • Hyman, C, Hoffer, M., Barde, Y.A., Juhasz, M., Yancopoulos, G.D., Squinto, S.P. and Linndsay, R.M. (1991) BDNF is a neurotrophic factor for dopamine neurons of the substantia nigra.Nature 350, 230–233.

    Article  PubMed  CAS  Google Scholar 

  • Isacson, P.J. (1995) Trophic factor response to neuronal stimuli or injury.Curr. Opi. Neurobiol. 5, 350–357.

    Article  Google Scholar 

  • Ito, A. and Horigone, K. (1995) Ceramide prevents neuronal programmed cell death induced by nerve growth factor deprivation.J. Neurochem. 65, 463–466.

    Article  PubMed  CAS  Google Scholar 

  • Janaky, R., Ogita, K., Pasqualotto, B.A., Bains, J.S., Oja, S.S., Yoneda, Y. and Shaw, C.A. (1999) Glutathione and signal transduction in the mammalian CNS.J. Neurochem. 73, 889–902.

    Article  PubMed  CAS  Google Scholar 

  • Jiao, S., Gurevich, V. and Wolff, J. A. (1993) Long term correction of rat model of Parkinson’s disease by gene therapy.Nature 362, 450–453.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan, D.R., Kempstead, B.L., Marti-Zanca, D., Chao, M.V. and Parada, L.F. (1991) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor.Science 252, 554–558.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan, D.R. and Stephens, R.M. (1994) Neurotrophin signal transduction by the Trk receptor.J. Neurobiol. 25, 1404- 1417.

    Article  PubMed  CAS  Google Scholar 

  • Kaczmarek, L.K. (1987) The role of protein kinase C in the regulation of ion channels and neurotransmitter release.TINS 10, 30–34.

    CAS  Google Scholar 

  • Klein, R., Nanduri, V, Jing, S., Lamballe, R, Tapley, P., Bryant, S., Cordon-Cardo, C, Jones, K.R., Reichardt, L.F. and Barbacid, M. (1991) The trk tyrosine protein kinase is a receptor for brain derived neurotrophic factor and neurotrophin-3.Cell 66, 395–403.

    Article  PubMed  CAS  Google Scholar 

  • Koh, S. and Loy, R. (1988) Age related loss of nerve growth factor sensitivity in rat basal forebrain neurons.Brain Res. 440, 396–401.

    Article  PubMed  CAS  Google Scholar 

  • Kordower, J.H., Mufson, E.J., Granholm, A.C., Hoffer, B. and Friden, P.M. (1993) Delivery of trophic factors to the primate brain.Exp. Neurol. 124, 21–30.

    Article  PubMed  CAS  Google Scholar 

  • Kordower, J.H., Chen, E.Y., Winkler, C, Fricker, R., Charles, V., Messing, A., Mufson, E.J., Wong, S.C., Rosenstein, J.M., Bjorklund, A., Emerich, D.F., Hammang, J. and Carpenter, M.K. (1997)J. Comp. Neurol. 387, 96–113.

    Article  PubMed  CAS  Google Scholar 

  • Knusel, B., Michel, P.P., Schwaber, J.S. and Hefti, F. (1990) Selective and non-selective stimulation of central cholinergic and dopaminergic developmentin vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factor I and II.J. Neurosci. 10, 558–570.

    PubMed  CAS  Google Scholar 

  • Knusel, B., Winslow, J.W., Rosenthal, A., Burton, L.E., Seid, D.P., Nikolics, K. and Hefti, F. (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin-3.Proc. Natl. Acad. Sci. USA 88, 961–965.

    Article  PubMed  CAS  Google Scholar 

  • Lapchack, P.A., Jiao, S., Miller, P.J., Williams, L.R., Cummins, V, Inouye, G., Matheson, C.R. and Yan, Q. (1996a) Pharmacological characterization of glial cell linederived neurotrophic factor (GDNF): implications for GDNF as a therapeutic molecule for treating neurodegenerative diseases.Cell Tissue Res. 286, 179–189.

    Article  Google Scholar 

  • Lapchack, P.A., Miller, P.J., Jiao, S., Araujo, D.M., Hilt, D. and Collins, F. (1996b) Biology of glial cell line-derived neurotrophic factor (GDNF): implications for the use of GDNF to treat Parkinson’s disease.Neurodegeneration 5, 197–205.

    Article  Google Scholar 

  • Lärkfors, L., Ebendal, T., Whittemore, S.R., Persson, H., Hoffer, B. and Olson, L. (1987) Decreased level of nerve growth factor (NGF) and its messenger RNA in aged rat brain.Mol. Brain Res. 3, 55–60.

    Article  Google Scholar 

  • Leibrock, J., Lottspelch, F., Hohn, A., Hofer, M., Hengerer, B., Masiakowski, P., Thoenen, H. and Barde, Y.A. (1989) Molecular cloning and expression of brain-derived neurotrophic factor.Nature 341, 149–152.

    Article  PubMed  CAS  Google Scholar 

  • Lendahl, U. and McKay, R.D. (1990) The use of cell lines in neurobiology13, 132–137.

    CAS  Google Scholar 

  • Levivier, M., Przedborski, S., Bensics, C. and Kang, U.J. (1995) Intrastriatal implantation of fibroblasts genetically engineered to produce brain derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease.J. Neurosci. 15, 7810–7820.

    PubMed  CAS  Google Scholar 

  • Levi Montalcini, R. (1951) Selective growth stimulating effects of mouse sarcomas on the sensory and sympathetic nervous system of chick embryos.J. Exp. Zool. 116, 321–362.

    Article  PubMed  CAS  Google Scholar 

  • Levi Montalcini, R. (1952) Effects of mouse tumor transplantation on the nervous system.Ann. N.Y. Acad. Sci. 55, 330–343.

    Article  PubMed  CAS  Google Scholar 

  • Levi Montalcini, R. (1966) The nerve growth factor: its mode of action on sensory and sympathetic nerve cells.Harvey Lect. 60, 217–259.

    PubMed  CAS  Google Scholar 

  • Levi Montalcini, R. (1987) The nerve growth factor thirty-five years later.Science 237, 1154–1162.

    Article  PubMed  CAS  Google Scholar 

  • Levi Montalcini, R. and Hamburger, V. (1951) Selective growth stimulating effects of mouse sarcoma, producing hyperplasia of sympathetic nervous system of the chick embryo.J. Exp. Zool. 116, 321–361.

    Article  PubMed  CAS  Google Scholar 

  • Lendahl, U. and McKay, R.D. (1990) The use of all lines in Neurobiology.Trends Neurosci. 8, 1085–1095.

    Google Scholar 

  • Levi Montalcini, R. and Angeletti, P.U. (1968) Nerve growth factor.Physiol. Rev. 48, 534–568.

    PubMed  CAS  Google Scholar 

  • Lin, L.F.H., Doherty, D.H., Lile, J.D., Bektesh, S. and Collins, F. (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.Science 260, 1130–1134.

    Article  PubMed  CAS  Google Scholar 

  • Lindner, M.D., Winn, S.R., Baetge, E.E., Hammang, J.P., Gentile, F.T., Doherty, E., Mcdermott, P.E., Frydel, B., Ullman, M.D. and Schallert, T. (1995) Implantation of encapsulated catecholamine and GDNF producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms.Exp. Neurol. 132, 62–76.

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Lozano, J.J., Bravo, G., Abascal, J., Brera, B., Pascual, MX., Martinez, R., De la Torre, C. and Moreno, R. (1996) Clinical experience with cotransplantation of peripheral nerve and adrenal medulla in patients with Parkinson’s disease.Transpl. Int. 9, 5485–5491.

    Article  Google Scholar 

  • MacKinnon, R.D., Matsui, T., Dubois-Dalq, M. and Aaronson, S.A. (1990) FGF modulates the PDGF-driven pathway of oligodendrocyte development.Neuron 5, 603–614.

    Article  Google Scholar 

  • Maisonpierre, P.C., Belluscio, L.B., Squinto, S., Ip, N.Y., Furth, M.E., Lindsay, R.M. and Yancopoulos, G.D. (1990a) Neurotrophin-3: a neurotrophic factor related to NGF and BDNF.Science 247, 1446–1451.

    Article  PubMed  CAS  Google Scholar 

  • Maisonpierre, P.C., Belluscio, L., Friedman, B., Alderson, R.F., Wiegand, S.J., Furth, M.E., Lindsay, R.M. and Yancopoulos, G.D. (1990b) NT3, BDNF, and NGF in the developing rat nervous system: Parallel as well as reciprocal patterns of expression.Neuron 5, 501–509.

    Article  PubMed  CAS  Google Scholar 

  • Mayer, E., Dunnett, S., Pellitteri, R. and Fawcett, J.W. (1993) Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons-1. Effectsin vitro.Neuroscience 56, 379–388.

    Article  PubMed  CAS  Google Scholar 

  • McGeer, E.G., Singh, E.A. and McGeer, P.L. (1992) Apparent anterograde transport of basic fibroblast growth factor in the rat nigrostriatal dopamine system.Neurosci. Lett. 148, 31–33.

    Article  PubMed  CAS  Google Scholar 

  • Mena, M.A., De Yebenes, J.G., Dwork, A., Latov, N., Fahn, S. and Herbert, J. (1987) Neuroblastoma cells as a possible donor for transplantation in animal models of Parkinson’s disease.Soc. Neurosci. Abstr. 13, (Abstract) 162.

    Google Scholar 

  • Mena, M.A., De Yebenes, J.G., Casarejos, M.J. and Pardo, B. (1988) The effects of growth factors, protein kinase activators and neurotoxins on catecholamine levels, cell size and mitotic rates in human neuroblastoma cells.Neurosci. Lett. 28, (Abstract) 90.

    Google Scholar 

  • Mena, M.A., De Yebenes, J.G., Dwork, A., Fahn, S., Latov, N., Herbert, J., Flaster, E. and Slonim, D. (1989a) Biochemical properties of monamine-rich human neuroblastoma cells.Brain Res. 486, 286–296.

    Article  PubMed  CAS  Google Scholar 

  • Mena, M.A., De Yebenes, J.G., Dwork, A., Goodman, R., Jamrosik, Z., Latov, N., Herbert, J. and Fahn, S. (1989b) Transplantes neuronales con celulas diferenciadas procedentes de neuroblastomas humanos en modelos expérimentales de enfermedad de Parkinson. In: Gimenez-Roldan, S. (Ed),Nuevas Estrategias Terapeuticas enla Enfermedad de Parkinson. Jarpyo editores, Madrid, Spain, pp. 63–79.

    Google Scholar 

  • Mena, M.A., Casarejos, M.J., Giménez-Gallego, G. and Garcia de Yebenes, J. (1995a) Fibroblast growth factors: structure-activity on dopamine neuronsin vitro. J. Neural. Transm. (P-D Sect)9, 1–14.

    Article  CAS  Google Scholar 

  • Mena, M.A., Casarejos, M.J. and Bonin, A. (1995b) Effects of dbcAMP and retinoic acid on the differentiation of dopamine neurons: prevention of cell death by dbcAMP.J. Neurochem. 65, 2612–2620.

    Article  PubMed  CAS  Google Scholar 

  • Mena, M.A., Casarejos, M.J., Carazo, A., Paino, C.L. and De Yebenes, J. (1997a). Glia protect fetal midbrain dopamine neurons in culture from L-DOPA toxicity through multiple mechanisms.J. Neural. Transm. 104, 317–328.

    Article  PubMed  CAS  Google Scholar 

  • Mena, M.A., Davila, V. and Sulzer, D. (1997b) Neurotrophic effects of L-DOPA in postnatal midbrain dopamine neuron/ cortical astrocytes cocultures.J. Neurochem. 69, 1398–1408.

    Article  PubMed  CAS  Google Scholar 

  • Mena, M.A., Davila, V., Bogaluvsky, J. and Sulzer, D. (1998) A synergistic neurotrophic response to L-DOPA and NGF.Mol Pharmacol. 54, 678–686.

    PubMed  CAS  Google Scholar 

  • Miettinen, P.J., Berger, J.E., Meneses, J. Phug Y., Pedersen, R.A., Werb, Z. and Derynck, R. (1995) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor.Nature 376, 337–341.

    Article  PubMed  CAS  Google Scholar 

  • Milbrandt, J., Sauvage, F.J., Fahrner, T.J., Baloh, R.H., Leitner, M.L., Tansey, M.G., Lampe, P.A. and Johnson, E.M. (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin.Neuron 20, 245–253.

    Article  PubMed  CAS  Google Scholar 

  • Morrison, R.S., Sharma, A., De Vellis, J. and Bradshaw, R.A. (1986) Basic fibroblast growth factor supports the survival of cerebral cortical neurons in primary culture.Proc. Natl. Acad. Sci. USA 83, 7537–7541.

    Article  PubMed  CAS  Google Scholar 

  • Morrison, R.S., Kornblum, H.I., Leslie, F.M. and Bradshaw, R.A. (1987) Trophic stimulation of cultured neurons from neonatal brain by epidermal growth factor.Science 238, 72–75.

    Article  PubMed  CAS  Google Scholar 

  • Mufson, E.J., Bothwell, M., Hersh, L.B. and Koedower, J.H. (1989) Nerve growth factor receptor immunoreactive profiles in the normal, aged human basal forebrain: colocalization with cholinergic neurons.J. Comp. Neurol. 285, 196–217.

    Article  PubMed  CAS  Google Scholar 

  • Nieto Sampedro, M., Lewis, E.R., Cotman, C.W., Manthorpe, M., Skaper, S.D., Barbin, G., Longo, F.M. and Varon, S. (1982) Brain injury causes a time-dependent increase in neuronotrophic activity at the lesion site.Science 2217, 860–861.

    Article  Google Scholar 

  • Nieto-Sampedro, M., Manthorpe, M., Barbin, G., Varon, S. and Cotman, C.W. (1983) Injury induced neuronotrophic activity in adult rat brain: correlation with survival of delayed implants in the wound cavity.J. Neurosci. 3, 2219–2229.

    PubMed  CAS  Google Scholar 

  • Nieto-Sampedro, M., Saneto, R.P., De Vellis, J. and Cotman, C.W. (1985) The control of glial populations in brain: changes in astrocyte mitogenic and morphologic factors in response to injury.Brain Res. 343, 320–328.

    Article  PubMed  CAS  Google Scholar 

  • Nistico, G., Ciriolo, M.R., Fiskin, K., Iannone, M., De Martino, A. and Rotilio, G. (1991) NGF restores decrease in catalase and increases glutathione peroxidase activity in the brain of aged rats.Neurosci. Lett. 130, 117–119.

    Article  PubMed  CAS  Google Scholar 

  • Nistico, G., Ciriolo, M.R., Fiskin, K., Iannone, M., De Martino, A. and Rotilio, G. (1992) NGF restores decrease in catalase activity and increase Superoxide dismutase and glutathione peroxidase activity in the brain of the aged rats.Free Rad. Biol. Medic. 12, 177–181.

    Article  CAS  Google Scholar 

  • Olson, L., Backlund, E.O., Ebendal, T., Freedman, R., Hamberger, B., Hansson, P., Hoffer, B.J., Lindblom, U., Meyerson, B., Strombergg, I., Sydow, O. and Seiger, A. (1991) Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson’s disease: one-year follow up of first clinical trial.Arch. Neurol. 48, 373–381.

    PubMed  CAS  Google Scholar 

  • Oppenheim, R.W., Prevette, D., Qin-Wei, Y, Collins, F. and MacDonald, J. (1990) Control of embryonic motoneuron survivalin vivo by ciliary neurotrophic factor.Science 251, 1616–1618.

    Article  Google Scholar 

  • Otto, D. and Unsicker, K. (1990) Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice.J. Neurosci. 10, 1912–1921.

    PubMed  CAS  Google Scholar 

  • Otto, D. and Unsicker, K. (1993) FGF-2 mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: specificity and impact of culture conditions, no dopaminergic neurons and astroglial cells.J. Neurosci. Res. 34, 382–393.

    Article  PubMed  CAS  Google Scholar 

  • Otto, D., Frotscher, M. and Unsicker, K. (1989) Basic fibroblast growth factor and nerve growth factor administered in gel foam rescue medial septal neurons after fimbria fornix transection.J. Neurosci. Res. 22, 83–91.

    Article  PubMed  CAS  Google Scholar 

  • Palfrey, C, Kimhi, Y and Littauer, U.Z. (1977) Induction of differentiation in mouse neuroblastoma cells.Biochem. Bioph. Res. Comm. 76, 937–942.

    Article  CAS  Google Scholar 

  • Palmer, T.D., Markakis, E.A., Wilhoite, A.R., Safar, F. and Gage, F.H. (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS.J. Neurosci. 19, 8487–8497.

    PubMed  CAS  Google Scholar 

  • Park, T.H. and Mytilineou, C. (1992) Protection from 1-methyl- 4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP+-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF.Brain Res. 599, 83–97.

    Article  PubMed  CAS  Google Scholar 

  • Pearce, R.K.B., Collins, P., Jenner, P., Emmett, C. and Marsden, CD. (1996) Intraventricular infusion of basic fibroblast growth factor (b-FGF) in the MPTP-treated common marmoset.Synapse 23, 192–200.

    Article  PubMed  CAS  Google Scholar 

  • Perez-Polo, J.R. (1985) Neuronotrophic factors. In: Bottenstein, J.E. and Sato, G. (Ed),Cell Cultures in the Neurosciences. Plenum Press, New-York, pp. 95–123.

    Google Scholar 

  • Pettmann, B., Weibel, M., Sensenbremer, M. and Labourdette, G. (1985) Purification of two astroglial growth factors from bovine brain.FEBS Lett. 189, 102–108.

    Article  PubMed  CAS  Google Scholar 

  • Pezzoli, G., Fahn, S., Dwork, A., Truong, D.D., De Yebenes, J.G., Jackson-Lewis, V, Herbert, J. and Cadet, J.L. (1988) Non-chromaffin tissue plus nerve growth factor reduces experimental parkinsonism in aged rats.Brain Res. 459, 398–403.

    Article  PubMed  CAS  Google Scholar 

  • Pezzoli, G., Zechinelli, A., Ricciardi, S., Burke, R., Fahn, S., Scarlato, G. and Garenzi, A. (1991) Intraventricular infusion of epidermal infusion of epidermal growth factor restores dopaminergic pathway in hemiparkinsonian rats.Mov. Disord. 6, 281–287.

    Article  PubMed  CAS  Google Scholar 

  • Publicover, S.J. (1985) Stimulation of spontaneous transmitter release by the phorbol ester, 12-O-tetradecanoylphorbol-13- acetate, an activator of protein kinase C.Brain Res. 333, 185–187.

    Article  PubMed  CAS  Google Scholar 

  • Rabin, S.J. and Mocchetti, I. (1995) GM1 ganglioside activates the high affinity nerve growth factortrk A.J. Neurochem. 65, 347–354.

    Article  PubMed  CAS  Google Scholar 

  • Ramón y Cajal, S. (1981) Recuerdos de mi vida: historia de mi labor científica. Alianza Universidad. 294–297.

  • Ramón y Cajal, S. (1991)Degeneration and Regeneration of the nervous system. R. May (Trad). 1928. Reedited by De Felipe, J. and Jones, E.G., Oxford University Press, Oxford.

    Google Scholar 

  • Recio Pinto, E. and Ishii, D.N. (1984) Effects of insulin, insulinlike growth factor II, and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells.Brain Res. 302, 323–334.

    Article  PubMed  CAS  Google Scholar 

  • Recio Pinto, E., Rechler, M.M. and Ishii, D.N. (1986) Effects of insulin, insulin-like growth factor II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons.J. Neurosci. 6, 1211–1219.

    PubMed  CAS  Google Scholar 

  • Reynolds, B. and Weiss, S. (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.Science 255, 1707–1710.

    Article  PubMed  CAS  Google Scholar 

  • Richardson, P.M. (1991) Neurotrophic factors in regeneration.Curr. Opi. Neurobiol. 1, 401–406.

    Article  CAS  Google Scholar 

  • Rosenblad, C, Kirik, D., Devaux, B., Moffat, B., Phillips, H.S. and Bjorklund, A. (1999) Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson’s disease after administration into the striatum or the lateral ventricle.Eur. J. Neurosci. 1, 1555–1566.

    Google Scholar 

  • Savage, C.R., Inagami, T. and Cohen, S. (1972) The primary structure of epidermal growth factor.J. Biol. Chem. 247, 7612–7621.

    PubMed  CAS  Google Scholar 

  • Scharr, D.G., Siebert, B.A., Dreyfus, C.F. and Black, I. (1993) Regional and cell-specific expression of GDNF in rat brain.Exp. Neurol. 124, 368–371.

    Article  Google Scholar 

  • Scott, J., Patterson, S., Rail, L., Bell, G.I., Crawford, R., Penschow, J., Niall, H. and Coghlan, J. (1985) The structure and biosynthesis of epidermal growth factor precursor.J. Cell Sci. 3, 19–28.

    CAS  Google Scholar 

  • Sendtner, M., Kreutzberg, G.W. and Thoenen, H. (1990) Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy.Nature 345, 440–441.

    Article  PubMed  CAS  Google Scholar 

  • Seroogy, K.B. and Gall, CM. (1993) Expression of neurotrophins by midbrain dopaminergic neurons.Exp. Neurol. 124, 119–128.

    Article  PubMed  CAS  Google Scholar 

  • Shults, C.W., Kimber, T. and Martin, D. (1996) Intrastriatal injection of GDNF attenuates the effects of 6-hydroxydopamine.NeuroReport 7, 627–631.

    Article  PubMed  CAS  Google Scholar 

  • Sievers, J., Hausmann, B., Unsicker, K. and Berry, M. (1987) Fibroblast growth factor promotes the survival of adult rat retinal ganglion cells after transection of the optic nerve.Neurosci. Lett. 76, 157–162.

    Article  PubMed  CAS  Google Scholar 

  • Silos-Santiago, I., Greenlund, L.J.S., Johnson, E.M. and Snider, W.D. (1995) Molecular genetics of neuronal survival.Curr. Opi. Neurobiol. 5, 42–49.

    Article  CAS  Google Scholar 

  • Snyder, E.Y. (1994) Grafting immortalized neurons to the SNC.Curr. Opin. Neurobiol. 4, 742–751.

    Article  PubMed  CAS  Google Scholar 

  • Snyder, S.H. (1991) Fresh factors to consider.Nature 350, 195–196.

    Article  PubMed  CAS  Google Scholar 

  • Spina, M.B., Squinto, S.P., Miller, J. and Hyman, C. (1992) Brain derived neurotrophic factor protects dopamine neurons against 6-hydroxy-dopamine and N-methyl-4-phenylpyr-idinium ion toxicity: involvement of the glutathione system.J. Neurochem. 59, 99–106.

    Article  PubMed  CAS  Google Scholar 

  • Spinelli, W, Sonnenfeld, K.H. and Ishii, D.N. (1982) Effects of phorbol ester tumor promoters and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells.Cancer Res. 42, 5067–5073.

    PubMed  CAS  Google Scholar 

  • Springer, J.E., Seeburger, J.L., He, J., Gabrea, A., Blankenhorn, E.P. and Bergman, L.W. (1995) cDNA sequence and differential mRNA regulation of two forms of glial cell line-derived neuro-trophic factor in Schwann cells and rat skeletal muscle.Exp. Neurol. 131, 47–52.

    Article  PubMed  CAS  Google Scholar 

  • Stromberg, I., Bjorklund, L., Johanson, M., Tomac, A., Collins, E, Olson, L. and Hoffer, C. (1993) Glial cell line-derived neuro-trophic factor (GDNF) is expressed in the developing but not adult striatum and stimulates developing dopamine neuronsin vivo.Exp. Neurol. 124, 401–412.

    Article  PubMed  CAS  Google Scholar 

  • Summerhill, E.M., Wood, K. and Fishman, M.C. (1987) Regulation of tyrosine hydroxylase gene expression during differentiation of neuroblastoma cells.Mol. Brain Res. 2, 99–103.

    Article  CAS  Google Scholar 

  • Tachikawa, E., Tank, A.W., Weiner, D.H., Mosimann, W.F., Yanagihara, N. and Weiner, N. (1987) Tyrosine hydroxylase is activated and phosphorylated on different sites in rat pheocromocytoma PC12 cells treated with phorbol ester and forskolin.J. Neurochem. 48, 1366–1376.

    Article  PubMed  CAS  Google Scholar 

  • Takayama, H., Ray, J., Raymon, H.K., Baird, A., Hogg, J., Fisher, L.J. and Gage, F.H. (1995) Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease.Nature Med. 153–158.

  • Tello, J.F. (1911) La influencia del neurotropismo en la regeneración de los centros nerviosos.Trab. Lab. Invest. Biol.,9, 123–159.

    Google Scholar 

  • Thomas, K.A. and Gimenez-Gallego, G. (1986) Fibroblast growth factors: broad spectrum mitogens with potent angiogenic activity.Trends Biochem. Sci. 11, 81–84.

    Article  CAS  Google Scholar 

  • Thompson, C.B. (1995) Apoptosis in the pathogenesis and treatment of disease.Science 267, 1456–1462.

    Article  PubMed  CAS  Google Scholar 

  • Thoenen, H. (1991) The changing scene of neurotrophic factors.TINS 14, 165–170.

    PubMed  CAS  Google Scholar 

  • Tischler, A.S., Lee, Y.C., Slayton, V.W. and Bloom, S.R. (1982) Content and release of neurotensin in PC12 pheochromocy- toma cell cultures: modulation by dexamethasone and nerve growth factor.Regul Pept. 3, 415–421.

    Article  PubMed  CAS  Google Scholar 

  • Tomac, A., Widenfalk, J., Lin, L.F., Kohno, T., Ebendal, T., Hoffer, B.J. and Olson, L. (1995) Retrograde axonal transport of glial cell line derived neurotrophic factor in the adult nigrostriatal system suggests a trophic role in the adult.Proc. Natl. Acad. Sci. USA 92, 8274–8278.

    Article  PubMed  CAS  Google Scholar 

  • Tooyama, I., McGeer, E.G., Kawamata, T., Kimura, H. and McGeer, P.L. (1994) Retention of fibroblast growth factor immunoreactivity in dopaminergic neurons of the substantia nigra during normal aging. Contrast with loss in Parkinson’s disease.Brain Res. 656, 165–168.

    Article  PubMed  CAS  Google Scholar 

  • Tooyama, I., Kawamata, T., Walker, D., Yamada, T., Hanai, K., Kimura, H., Iwane, M., Igarashi, K., McGeer, E.G. and McGeer, P.L. (1993) Loss of basic fibroblast growth factor in substantia nigra neurons in Parkinson’s disease.Neurology 43, 372–376.

    PubMed  CAS  Google Scholar 

  • Tooyama, I., Walker, D., Yamada, T., Hanai, K., Kimura, H., McGeer, E.G. and McGeer, P.L. (1992) High molecular weight basic fibroblast growth factor-like protein is localized to a subpopulation of mesencephalic dopaminergic neurons in the rat brain.Brain Res. 593, 274–280.

    Article  PubMed  CAS  Google Scholar 

  • Traynor, A.E., Schubert, D. and Allen, W.R. (1982) Alterations of lipid metabolism in response to nerve growth factor.J. Neurochem. 39, 1677–1683.

    Article  PubMed  CAS  Google Scholar 

  • Trupp, M., Ryden, M., Jonwall, H., Funakoshi, H., Timmusk, T., Arenas, E. and Ibañez, CF. (1995) Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons.J. Cell Biol. 130, 137–148.

    Article  PubMed  CAS  Google Scholar 

  • Tsukahara, T., Takeda, M., Shimohama, S., Ohara, O. and Hashimoto, N. (1995) Effects of brain-derived neurotrophic factor on l-methyl-4-phenyl-l,2,3,6,tetrahydropyri-dine-induced parkinsonism in monkeys.Neurosurgery 37, 733–739.

    Article  PubMed  CAS  Google Scholar 

  • Unsicker, K., Reichert-Preibshch, H., Schmidt, R., Pettman, B., Labourdette, G. and Sensenbremer, M. (1987) Astroglial and fibroblast growth factors have neurotrophic functions for cultured peripheral and central nervous system neurons.Proc. Natl. Acad. Sci. USA 84, 5459–5463.

    Article  PubMed  CAS  Google Scholar 

  • Unsicker, K., Seidl, K. and Hofmann, H.D. (1989) The neuroendocrine ambiguity of the sympatoadrenal cells.Int. J. Dev. Neurosci. 7, 413–417.

    Article  PubMed  CAS  Google Scholar 

  • Unsicker, K., Reichert-Preibsch, H. and Wewetzer, K. (1992) Stimulation of neuron survival by basic FGF and CNTF is a direct effect and not mediated by non-neuronal cells: evidence from single cell cultures.Dev. Brain Res. 65, 285–288.

    Article  CAS  Google Scholar 

  • Ventrella, L.L. (1993) Effect of intracerebroventricular infusion of epidermal growth factor in rats hemitransected in the nigro-striatal pathway.J. Neurosurg. Sci. 37, 1–8.

    PubMed  CAS  Google Scholar 

  • Volpe, B.T., Wildmann, J. and Altar, C.A. (1998) Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions.Neuroscience 83, 741–748.

    Article  PubMed  CAS  Google Scholar 

  • Walicke, P., Cowan, W.M., Ueno, N., Baird, A. and Guillemin, R. (1986) Fibroblast growth factor promotes survival of dissociated hippocampal neurons and enhances neurote extension.Proc. Natl. Acad. Sci. USA 83, 3012–3016.

    Article  PubMed  CAS  Google Scholar 

  • Walicke, P.A. and Baird, A. (1988) Trophic effects of fibroblast growth factor on neural tissue. In: Gash, D.M. and Sladek, J.R. (Eds).Transplantation into the Mammalian CNS. Progress in brain research 78. Elsevier, New York, pp. 333–338.

    Google Scholar 

  • Walicke, P.A. (1988) Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions.J. Neurosci. 8, 2618–2627.

    PubMed  CAS  Google Scholar 

  • Wanaka, A., Johnson, E.M. and Milbrandt, J. (1990) Localization of FGF receptor mRN A in the adult rat central nervous system byin situ hybridization.Neuron 5, 267–281.

    Article  PubMed  CAS  Google Scholar 

  • Wang, J., Bankiewicz, K.S., Plunkett, R.J. and Oldfield, E.H. (1994) Intrastriatal implantation of interleukin-1. Reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral teg- mental area of the mid brain.J. Neurosug. 80, 484–490.

    Article  CAS  Google Scholar 

  • Yoshimoto, Y, Lin, Q., Collier, T.J., Frim, D.M., Breakefield, X.O. and Bohn, M.C. (1995) Astrocytes retrovirally transduced with BDNF elicit behaviorally improvement in a rat model of Parkinson’s disease.Brain Res. 11, 25–36.

    Article  Google Scholar 

  • Yurek, D.M., Lu, W., Hipkens, S. and Wiegand, S.J. (1996) BDNF enhances the functional reinnervation of the striatum by grafted fetal dopamine neurons.Exp. Neurol. 137, 105–118.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, W., Lee, W.H. and Triarhou, L.C. (1996) Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function.Nature Med. 2, 65–71.

    Article  PubMed  CAS  Google Scholar 

  • Zurgil, N. and Zisapel, N. (1985) Phorbol ester and calcium act synergistically to enhance neurotransmitter release by brain neurons in culture.FEES 185, 257–261.

    Article  CAS  Google Scholar 

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  1. Servicio de Neurologia, Fundacion Jimenez Diaz, Avda de Reyes Catolicos, 2, 28040, Madrid, Spain

    Justo Garcia de Yebenes & Maria Angeles Mena

  2. Departamento de Investigation, Hospital Ramon y Cajal, Madrid, Spain

    Justo Garcia de Yebenes & Maria Angeles Mena

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de Yebenes, J.G., Mena, M.A. Neurotrophic factors in neurodegenerative disorders: Model of parkinson’s disease. neurotox res 2, 115–137 (2000). https://doi.org/10.1007/BF03033789

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