Abstract
The adult brain requires a constant trophic input for appropriate function. Although the main source of trophic factors for mature neurons is considered to arise locally from glial cells and synaptic partners, recent evidence suggests that hormonal-like influences from distant sources may also be important. These include not only relatively well-characterized steroid hormones that cross the brain barriers, but also blood-borne protein growth factors able to cross the barriers and exert unexpected, albeit specific, trophic actions in diverse brain areas. Insulin-like growth factor I (IGF-I) is until now the serum neurotrophic factor whose actions on the adult brain are best-characterized. This is because IGF-I has been known for many years to be present in serum, whereas the presence in the circulation of other more classical neurotrophic factors has only recently been recognized. Thus, new evidence strongly suggests that IGF-I, and other blood-borne neurotrophic factors such as Fibroblast Growth Factor (FGF-2) or the neurotrophins, exert a tonic trophic input on brain cells, providing a mechanism for what we may refer to as neuroprotective surveillance. Protective surveillance includes “first-line” defense mechanisms ranging from blockade of neuronal death after a wide variety of cellular insults to upregulation of neurogenesis when defenses against neuronal death are overcome. Most importantly, surveillance should also encompass modulation of homeostatic mechanisms to prevent neuronal derangement. These will include modulation of basic cellular processes such as metabolic demands and maintainance of cell-membrane potential as well as more complex processes such as regulation of neuronal plasticity to keep neurons able to respond to constantly changing functional demands.
Similar content being viewed by others
References
Walz W. (1989) Role of glial cells in the regulation of the brain ion microenvironment. Prog. Neurobiol. 33, 309–333.
Rubin L. L. and Staddon J. M. (1999) The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22, 11–28.
Strazielle N. and Ghersi-Egea J. F. (2000) Choroid plexus in the central nervous system: biology and physiopathology. J. Neuropathol. Exp. Neurol. 59, 561–574.
Isackson P. J. (1995) Trophic factor response to neuronal stimuli or injury. Curr. Opin. Neurobiol. 5, 350–357.
Morganti-Kossman M. C., Lenzlinger P. M., Hans V., Stahel P., Csuka E., Ammann E., et al. (1997) Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol. Psychiatry 2, 133–136.
Murphy R. A., Saide J. D., Blanchard M. H., and Young M. (1977). Nerve growth factor in mouse serum and saliva: role of the submandibular gland. Proc. Natl. Acad. Sci. USA 74, 2330–2333.
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.
Nakahashi T., Fujimura H., Altar C. A., Li J., Kambayashi J., Tandon N. N., and Sun B. (2000) Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 470, 113–117.
Gilmore J. H., Jarskog L. F., Lindgren J. C., McEvoy J. P., and Xiao H. (1997) Neurotrophin-3 levels in the cerebrospinal fluid of patients with schizophrenia or medical illness. Psychiatry Res. 73, 109–113.
Hock C., Heese K., Muller-Spahn F., Huber P., Riesen W., Nitsch R. M., and Otten U. (2000) Increased CSF levels of nerve growth factor in patients with Alzheimer’s disease. Neurology 54, 2009–2011.
Kossmann T., Stahel P. F., Lenzlinger P. M., Redl H., Dubs R. W., Trentz O., et al. (1997) Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J. Cereb. Blood Flow Metab. 17, 280–289.
Laudiero L. B., Aloe L., Levi-Montalcini R., Buttinelli C., Schilter D., Gillessen S., and Otten U. (1992) Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci. Lett. 147, 9–12.
Malek A. M., Connors S., Robertson R. L., Folkman J., and Scott R. M. (1997) Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatr. Neurosurg. 27, 182–189.
Mizuno Y., Takada H., Urakami K., Ihara K., Kira R., Suminoe A., et al. (2000) Neurotrophin-3 levels in cerebrospinal fluid from children with bacterial meningitis, viral meningitis, or encephalitis. J. Child. Neurol. 15, 19–21.
Mogi M. and Nagatsu T. (1999) Neurotrophins and cytokines in Parkinson’s disease. Adv. Neurol. 80, 135–139.
Patterson S. L., Grady M. S., and Bothwell M. (1993) Nerve growth factor and a fibroblast growth factor-like neurotrophic activity in cerebrospinal fluid of brain injured human patients. Brain Res. 605, 43–49.
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. Park Dis. Dement. Sect. 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.
Busiguina S., Fernandez A. M., Barrios V., Clark R., Tolbert D. L., Berciano J., and Torres-Aleman I. (2000) Neurodegeneration is associated to changes in serum insulin-like growth factors. Neurobiol. Dis. 7, 657–665.
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.
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.
Deguchi Y., Naito T., Yuge T., Furukawa A., Yamada S., Pardridge W. M., and Kimura R. (2000) Blood-brain barrier transport of 125I-labeled basic fibroblast growth factor. Pharm. Res. 17, 63–69.
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.
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.
Reinhardt R. R. and Bondy C. A. (1994) Insulinlike growth factors cross the blood-brain barrier. Endocrinology 135, 1753–1761.
Stewart P. A. (2000) Endothelial vesicles in the blood-brain barrier: are they related to permeability? Cell Mol. Neurobiol. 20, 149–163.
Ferguson I. A., Schweitzer J. B., Bartlett P. F., and Johnson E. M., Jr. (1991) Receptor-mediated retrograde transport in CNS neurons after intraventricular administration of NGF and growth factors. J. Comp Neurol. 313, 680–692.
Ferry R. J., Jr., Katz L. E., Grimberg A., Cohen P., and Weinzimer S. A. (1999) Cellular actions of insulin-like growth factor binding proteins. Horm. Metab Res. 31, 192–202.
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.
Armstrong C. S., Wuarin L., and Ishii D. N. (2000) Uptake of circulating insulin-like growth factor-I into the cerebrospinal fluid of normal and diabetic rats and normalization of IGF-II mRNA content in diabetic rat brain. J. Neurosci. Res. 59, 649–660.
Pulford B. E., Whalen L. R., and Ishii D. N. (1999) Peripherally administered insulin-like growth factor-I preserves hindlimb reflex and spinal cord noradrenergic circuitry following a central nervous system lesion in rats. Exp. Neurol. 159, 114–123.
Wagner J. P., Black I. B., and DiCicco-Bloom E. (1999) Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J. Neurosci. 19, 6006–6016.
Jones J. I. and Clemmons D. R. (1995) Insulinlike growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34.
Yakar S., Liu J. L., Stannard B., Butler A., Accili D., Sauer B., and LeRoith D. (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl. Acad. Sci. USA 96, 7324–7329.
Ueki I., Ooi G. T., Tremblay M. L., Hurst K. R., Bach L. A., and Boisclair Y. R. (2000) Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. Proc. Natl. Acad. Sci. USA 97, 6868–6873.
Schechter R., Holtzclaw L., Sadiq F., Kahn A., and Devaskar S. (1988) Insulin synthesis by isolated rabbit neurons. Endocrinology 123, 505–513.
Pardridge W. M. (1993) Transport of insulinrelated peptides and glucose across the bloodbrain barrier. Ann. NY Acad. Sci. 692, 126–137.
Poduslo J. F., Curran G. L., and Berg C. T. (1994) Macromolecular permeability across the bloodnerve and blood-brain barriers. Proc. Natl. Acad. Sci. USA 91, 5705–5709.
Bondy C. A., Werner H., Roberts C. T., Jr., and LeRoith D. (1990) Cellular pattern of insulinlike growth factor-I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol. Endocrinol. 4, 1386–1398.
Golden P. L., Maccagnan T. J., and Pardridge W. M. (1997) Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J. Clin. Invest. 99, 14–18.
Timmusk T., Mudo G., Metsis M., and Belluardo N. (1995) Expression of mRNAs for neurotrophins and their receptors in the rat choroid plexus and dura mater. Neuroreport 6, 1997–2000.
Moos T. and Morgan E. H. (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol. Neurobiol. 20, 77–95.
Aguado F., Rodrigo J., Cacicedo L., and Mellstrom B. (1993) Distribution of insulin-like growth factor-I receptor mRNA in rat brain. Regulation in the hypothalamo-neurohypophysial system. J. Mol. Endocrinol. 11, 231–239.
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.
Bach M. A., Shen-Orr Z., Lowe W. L., Jr., Roberts C. T., Jr., and LeRoith D. (1991) Insulinlike growth factor I mRNA levels are developmentally regulated in specific regions of the rat brain. Brain Res. Mol. Brain Res. 10, 43–48.
Pons S., Rejas M. T., and Torres-Aleman I. (1991) Ontogeny of insulin-like growth factor I, its receptor, and its binding proteins in the rat hypothalamus. Brain Res. Dev. Brain Res. 62, 169–175.
Torres-Aleman I., Pons S., and Arevalo M. A. (1994) The insulin-like growth factor I system in the rat cerebellum: developmental regulation and role in neuronal survival and differentiation. J. Neurosci. Res. 39, 117–126.
van Praag H., Christie B. R., Sejnowski T. J., and Gage F. H. (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96, 13,427–13,431.
Neeper S. A., Gomez-Pinilla F., Choi J., and Cotman C. W. (1996) Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain. Brain Res. 726, 49–56.
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.
Fernandez A. M., Gonzalez de la Vega A. G., Planas B., and Torres-Aleman I. (1999) Neuroprotective actions of peripherally administered insulin-like growth factor I in the injured olivocerebellar pathway. Eur. J. Neurosci. 11, 2019–2030.
Mitchell J. J., Paiva M., Walker D. W., and Heaton M. B. (1999) BDNF and NGF afford in vitro neuroprotection against ethanol combined with acute ischemia and chronic hypoglycemia. Dev. Neurosci. 21, 68–75.
Black I. B. (1999) Trophic regulation of synaptic plasticity. J. Neurobiol. 41, 108–118.
Schuman E. (1997) Growth factors sculpt the synapse. Science 275, 1277, 1278.
Purves D. (1980) Neuronal competition. Nature 287, 585, 586.
Lee W. H., Javedan S., and Bondy C. A. (1992) Coordinate expression of insulin-like growth factor system components by neurons and neuroglia during retinal and cerebellar development. J. Neurosci. 12, 4737–4744.
Nieto-Bona M. P., Busiguina S., and Torres-Aleman I. (1995) Insulin-like growth factor I is an afferent trophic signal that modulates calbindin-28kD in adult Purkinje cells. J. Neurosci. Res. 42, 371–376.
Torres-Aleman, I., Pons S., and Garcia-Segura L. M. (1991) Climbing fiber deafferentation reduces insulin-like growth factor I (IGF-I) content in cerebellum. Brain Res. 564, 348–351.
Satake S., Saitow F., Yamada J., and Konishi S. (2000) Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons. Nat. Neurosci. 3, 551–558.
Garcia-Segura L. M., Rodriguez J. R., and Torres-Aleman I. (1997) Localization of the insulinlike growth factor I receptor in the cerebellum and hypothalamus of adult rats: an electron microscopic study. J. Neurocytol. 26, 479–490.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Torres-Aleman, I. Serum growth factors and neuroprotective surveillance. Mol Neurobiol 21, 153–160 (2000). https://doi.org/10.1385/MN:21:3:153
Issue Date:
DOI: https://doi.org/10.1385/MN:21:3:153