Abstract
The existence of protective mechanisms in the adult brain is gradually being recognized as an important aspect of brain function. For many years, self-repair processes in the post-embryonic brain were considered of minor consequence or nonexistent. This notion dominated the study of neurotrophism. Thus, although the possibility that neurotrophic factors participate in brain function in adult life was prudently maintained, the majority of the studies on the role of trophic factors in the brain were focused on developmental aspects. With the recent recognition that the adult brain keeps a capacity for cell renewal, although limited, a new interest in the regenerative properties of brain tissue has emerged. New findings on the role of insulin-like growth factor I (IGF-I), a potent neurotrophic peptide present at high levels in serum, may illustrate this current trend. Circulating IGF-I is an important determinant of proper brain function in the adult. Its pleiotropic effects range from classical trophic actions on neurons such as housekeeping or anti-apoptotic/pro-survival effects to modulation of brain-barrier permeability, neuronal excitability, or new neuron formation. More recent findings indicate that IGF-I participates in physiologically relevant neuroprotective mechanisms such as those triggered by physical exercise. The increasing number of neurotrophic features displayed by serum IGF-I reinforces the view of a physiological neuroprotective network formed by IGF-I, and possibly other still uncharacterized signals. Future studies with IGF-I, and hopefully other neurotrophic factors, will surely reveal and teach us how to potentiate the self-reparative properties of the adult brain.
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References
Jones J. I. and Clemmons D. R. (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34.
LeRoith D. and Roberts C. T., Jr. (1993) Insulin-like growth factors. Ann. NY Acad. Sci. 692, 1–9.
Sjogren K., Liu J. L., Blad K., Skrtic S., Vidal O., Wallenius V., et al. (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Natl. Acad. Sci. USA 96, 7088–7092.
Yakar S., Liu J. L., Stannard B., Butler A., Accili D., Sauer B., et al. (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 96, 7324–7329.
Feldman E. L., Sullivan K. A., Kim B., and Russell J. W. (1997) Insulin-like growth factors regulate neuronal differentiation and survival. Neurobiol. Dis. 4, 201–214.
Torres-Aleman I. (1999) Insulin-like growth factors as mediators of functional plasticity in the adult brain. Horm. Metab. Res. 31, 114–119.
Busiguina S., Fernandez A. M., Barrios V., Clark R., Tolbert D. L., Berciano J., et al. (2000) Neurodegeneration is associated to changes in serum insulin-like growth factors. Neurobiol. Dis. 7, 657–665.
Mustafa A., Lannfelt L., Lilius L., Islam A., Winblad B., and Adem A. (1999) Decreased plasma insulin-like growth factor-I level in familial Alzheimer’s disease patients carrying the Swedish APP 670/671 mutation. Dement. Geriatr. Cogn. Disord. 10, 446–451.
Schwab S., Spranger M., Krempien S., Hacke W., and Bettendorf M. (1997) Plasma insulin-like growth factor I and IGF binding protein 3 levels in patients with acute cerebral ischemic injury. Stroke 28, 1744–1748.
Tham A., Nordberg A., Grissom F. E., Carlsson-Skwirut C., Viitanen M., and Sara V. R. (1993) Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type. J. Neural Transm. 5, 165–176.
Torres-Aleman I., Barrios V., Lledo A., and Berciano J. (1996) The insulin-like growth factor I system in cerebellar degeneration. Ann. Neurol. 39, 335–342.
Torres-Aleman I., Barrios V., and Berciano J. (1998) The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis. Neurology 50, 772–776.
Carro E., Nunez A., Busiguina S., and Torres-Aleman I. (2000) Circulating insulin-like growth factor I mediates effects of exercise on the brain. J. Neurosci. 20, 2926–2933.
Fernandez A. M., de la Vega A. G., and Torres-Aleman I. (1998) Insulin-like growth factor I restores motor coordination in a rat model of cerebellar ataxia. Proc. Natl. Acad. Sci. USA 95, 1253–1258.
Torres-Aleman I. (2000) Serum growth factors and neuroprotective surveillance. Mol. Neurobiol. 21, 153–160.
Mason J. L., Suzuki K., Chaplin D. D., and Matsushima G. K. (2001) Interleukin-1beta promotes repair of the CNS. J. Neurosci. 21, 7046–7052.
Solerte S. B., Cravello L., Ferrari E., and Fioravanti M. (2000) Overproduction of IFN-gamma and TNF-alpha from natural killer (NK) cells is associated with abnormal NK reactivity and cognitive derangement in Alzheimer’s disease. Ann. NY Acad. Sci. 917, 331–340.
Rubin L. L. and Staddon J. M. (1999) The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22, 11–28.
Poduslo J. F., Curran G. L., and Berg C. T. (1994) Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc. Natl. Acad. Sci. USA 91, 5705–5709.
Reinhardt R. R. and Bondy C. A. (1994) Insulin-like growth factors cross the blood-brain barrier. Endocrinology 135, 1753–1761.
Banks W. A., Kastin A. J., Huang W., Jaspan J. B., and Maness L. M. (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305–311.
Banks W. A., Jaspan J. B., and Kastin A. J. (1997) Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 18, 1257–1262.
Deguchi Y., Naito T., Yuge T., Furukawa A., Yamada S., Pardridge W. M., et al. (2000) Blood-brain barrier transport of 125I-labeled basic fibroblast growth factor. Pharm. Res. 17, 63–69.
Pan W., Banks W. A., Fasold M. B., Bluth J., and Kastin A. J. (1998) Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37, 1553–1561.
Pan W., Banks W. A., and Kastin A. J. (1998) Permeability of the blood-brain barrier to neurotrophins. Brain Res. 788, 87–94.
Pan W. and Kastin A. J. (1999) Entry of EGF into brain is rapid and saturable. Peptides 20, 1091–1098.
Pan W., Kastin A. J., Maness L. M., and Brennan J. M. (1999) Saturable entry of ciliary neurotrophic factor into brain. Neurosci. Lett. 263, 69–71.
Poduslo J. F. and Curran G. L. (1996) Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res. Mol. Brain Res. 36, 280–286.
Bondy C. A. and Lee W. H. (1993) Patterns of insulin-like growth factor and IGF receptor gene expression in the brain. Functional implications. Ann. NY Acad. Sci. 692, 33–43.
Rita P. (1993) Nonsynaptic diffusion neurotransmission (NDN) in the brain. Neurochem. Int. 23, 297–318.
Pardridge W. M. (2002) Targeting neurotherapeutic agents through the blood-brain barrier. Arch. Neurol. 59, 35–40.
Jones J. I., Gockerman A., Busby W. H. Jr., Wright G., and Clemmons D. R. (1993) Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the alpha 5 beta 1 integrin by means of its Arg-Gly-Asp sequence. Proc. Natl. Acad. Sci. USA 90, 10,553–10,557.
Blau H. M., Brazelton T. R., and Weimann J. M. (2001) The evolving concept of a stem cell: entity or function? Cell 105, 829–841.
Aberg M. A., Aberg N. D., Hedbacker H., Oscarsson J., and Eriksson P. S. (2000) Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J. Neurosci. 20, 2896–2903.
Trejo J. L., Carro E., and Torres-Aleman I. (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634.
Castro-Alamancos M. A. and Torres-Aleman I. (1993) Long-term depression of glutamate-induced gamma-aminobutyric acid release in cerebellum by insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 90, 7386–7390.
Thoenen H. (1995) Neurotrophins and neuronal plasticity. Science 270, 593–598.
Chang S. and Popov S. V. (1999) Long-range signaling within growing neurites mediated by neurotrophin-3. Proc. Natl. Acad. Sci. USA 96, 4095–4100.
Desai N. S., Rutherford L. C., and Turrigiano G. G. (1999) BDNF regulates the intrinsic excitability of cortical neurons. Learn. Mem. 6, 284–291.
Wang Y. T. and Linden D. J. (2000) Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25, 635–647.
Castro-Alamancos M. A. and Torres-Aleman I. (1994) Learning of the conditioned eye-blink response is impaired by an antisense insulin-like growth factor I oligonucleotide. Proc. Natl. Acad. Sci. USA 91, 10,203–10,207.
Al Majed A. A., Neumann C. M., Brushart T. M., and Gordon T. (2000) Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J. Neurosci. 20, 2602–2608.
Prolla T. A. and Mattson M. P. (2000) Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends Neurosci. 24, S31.
Blair L. A. and Marshall J. (1997) IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner. Neuron 19, 421–429.
De Luca A., Pierno S., Liantonio A., Camerino C., and Conte C. D. (1998) Phosphorylation and IGF-1-mediated dephosphorylation pathways control the activity and the pharmacological properties of skeletal muscle chloride channels. Br. J. Pharmacol. 125, 477–482.
Gonzalez de la Vega A., Buno W., Pons S., Garcia-Calderat M. S., Garcia-Galloway E., and Torres-Aleman I. (2001) Insulin-like growth factor I potentiates kainate receptors through a phosphatidylinositol 3-kinase dependent pathway. Neuroreport 12, 1293–1296.
Kanzaki M., Zhang Y. Q., Mashima H., Li L., Shibata H., and Kojima I. (1999) Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-I. Nat. Cell Biol. 1, 165–170.
Kelsch W., Hormuzdi S., Straube E., Lewen A., Monyer H., and Misgeld U. (2001) Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of hippocampal neurons. J. Neurosci. 21, 8339–8347.
Man Y. H., Lin J. W., Ju W. H., Ahmadian G., Liu L., Becker L. E., et al. (2000) Regulation of AMPA receptor-mediated synaptic transmission by clathrin- dependent receptor internalization. Neuron 25, 649–662.
Sakagami K., Wu D. M., and Puro D. G. (1999) Physiology of rat retinal pericytes: modulation of ion channel activity by serum-derived molecules. J. Physiol. 521, Pt 3, 637–650.
Savchenko A., Kraft T. W., Molokanova E., and Kramer R. H. (2001) Growth factors regulate phototransduction in retinal rods by modulating cyclic nucleotide-gated channels through dephosphorylation of a specific tyrosine residue. Proc. Natl. Acad. Sci. USA 98, 5880–5885.
Shanley L. J., Irving A. J., Rae M. G., Ashford M. L., and Harvey J. (2002) Leptin inhibits rat hippocampal neurons via activation of large conductance calcium-activated K+ channels. Nat. Neurosci. 5, 299–300.
Yang F., Feng L., Zheng F., Johnson S. W., Du J., Shen L., et al. (2001) GDNF acutely modulates excitability and A-type K(+) channels in midbrain dopaminergic neurons. Nat. Neurosci. 4, 1071–1078.
Arsenijevic Y., Weiss S., Schneider B., and Aebischer P. (2001) Insulin-like growth factor-1 is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. J. Neurosci. 21, 7194–7202.
Anderson M. F., Aberg M. A., Nilsson M., and Eriksson P. S. (2002) Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res. Dev. Brain Res. 134, 115–122.
Cameron H. A. and McKay R. D. (2001) Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417.
Carro E., Trejo J. L., Busiguina S., and Torres-Aleman I. (2001) Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. J. Neurosci. 21, 5678–5684.
Armstrong R. J. and Barker R. A. (2001) Neurodegeneration: a failure of neuroregeneration? Lancet 358, 1174–1176.
Arsenijevic Y., Villemure J. G., Brunet J. F., Bloch J. J., Deglon N., Kostic C., et al. (2001) Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp. Neurol. 170, 48–62.
Magavi S. S., Leavitt B. R., and Macklis J. D. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955.
Lundberg C., Martinez-Serrano A., Cattaneo E., McKay R. D., and Bjorklund A. (1997) Survival, integration, and differentiation of neural stem cell lines after transplantation to the adult rat striatum. Exp. Neurol. 145, 342–360.
Peterson D. A. (2002) Stem cells in brain plasticity and repair. Curr. Opin. Pharmacol. 2, 34–42.
Roelen C. A., de Vries W. R., Koppeschaar H. P., Vervoorn C., Thijssen J. H., and Blankenstein M. A. (1997) Plasma insulin-like growth factor-I and high affinity growth hormone-binding protein levels increase after two weeks of strenuous physical training. Int. J. Sports Med. 18, 238–241.
Wallace J. D., Cuneo R. C., Baxter R., Orskov H., Keay N., Pentecost C., et al. (1999) Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport. J. Clin. Endocrinol. Metab. 84, 3591–3601.
Anthony T. G., Anthony J. C., Lewitt M. S., Donovan S. M., and Layman D. K. (2001) Time course changes in IGFBP-1 after treadmill exercise and postexercise food intake in rats. Am. J. Physiol. 280, E650-E656.
Eliakim A., Brasel J. A., Mohan S., Wong W. L., and Cooper D. M. (1998) Increased physical activity and the growth hormone-IGF-I axis in adolescent males. Am. J. Physiol. 275, R308-R314.
Eliakim A., Moromisato M., Moromisato D., Brasel J. A., Roberts C., and Cooper D. M. (1997) Increase in muscle IGF-I protein but not IGF-I mRNA after 5 days of endurance training in young rats. Am. J. Physiol. 273, R1557-R1561.
Kramer A. F., Hahn S., Cohen N. J., Banich M. T., McAuley E., Harrison C. R., et al. (1999) Ageing, fitness and neurocognitive function. Nature 400, 418–419.
Larsen J. O., Skalicky M., and Viidik A. (2000) Does long-term physical exercise counteract age-related purkinje cell loss? A stereological study of rat cerebellum. J. Comp. Neurol. 428, 213–222.
Neeper S. A., Gomez-Pinilla F., Choi J., and Cotman C. (1995) Exercise and brain neurotrophins. Nature 373, 109.
Radaka Z., Kanekob T., Taharab S., Nakamotoc H., Pucsokd J., Sasvarie M., et al. (2001) Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem. Int. 38, 17–23.
van Praag H., Kempermann G., and Gage F. H. (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270.
Thoenen H. (2000) Neurotrophins and activity-dependent plasticity. Prog. Brain Res. 128, 183–191.
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Carro, E., Trejo, J.L., Núñez, A. et al. Brain repair and neuroprotection by serum insulin-like growth factor I. Mol Neurobiol 27, 153–162 (2003). https://doi.org/10.1385/MN:27:2:153
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DOI: https://doi.org/10.1385/MN:27:2:153