Insulin-like growth factor-1 (IGF-1): a neuroprotective trophic factor acting via the Akt kinase pathway
Insulin-like growth factor-I (IGF-I) is a pleiotropic polypeptide with a wide range of actions in both central and peripheral nervous sytems. Over the past few years, we studied the trophic as well as neuromodulatory roles of IGF-I in the brain. Accumulat
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Summary. Insulin-like growth factor-I (IGF-I) is a pleiotropic polypeptide with a wide range of actions in both central and peripheral nervous sytems. Over the past few years , we studied the trophic as well as neuromodulatory roles of IGF-I in the brain. Accumulated evidence indicates that IGF-I, apart from regulating growth and development, protects neurons against cell death induced by amyloidogenic derivatives, glucose or serum deprivation via the activation of intracellular pathways implicating phosphatidylinositide 3/Akt kinase, winged-helix family of transcription factor FKHRL1 phosphorylation or production of free radicals. The effects of IGF-I on neuroprotection, glucose metabolism and activity-dependent plasticity suggest the potential usefulness of this growth factor or related mimetics in the treatment of Alzheimer's disease and other neurodegenerative disorders. Introduction
Insulin-like growth factor-I (IGF-I), known earlier as sulfation factor or somatomedin C, was discovered in 1957. The precise action of IGF-I was, however, poorly understood until the production of recombinant human IGFI in the 1980s. It is now well established that IGF-I mediates the action of growth hormone (Isaksson et al., 1991), plays an important role in the development of bone and cartilage (Johansson et al., 1993) as well as in the repair process in arthritic patients (Dore et al., 1994). IGF-I is found in high levels in the blood and believed to originate mainly from the liver (Pankov, 1999). Subsequent gene expression studies revealed its detection in several organs including the brain (Rotwein et al., 1988). The structure of IGF-I, a peptide with 70 amino acids, is very much similar to that of insulin (Isaksson et al., 1991). Interestingly, given the evidence that insulin level in the brain is quite low, it is suggested that IGF-I could exert insulin-like activity in the central nervous system. This is supported, in part, by the evidence that IGF-I can bind to the family of IGF-like receptors including the insulin receptor. Additionally, IGF-I has been shown to bind IGF binding proteins (IGFBPs), which are expressed at relatively lower levels in the ner-
P. Riederer et al. (eds.), Advances in Research on Neurodegeneration © Springer-Verlag Wien 2000
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W.-H. Zheng et al.
vous system than in the periphery (Clemmons, 1998). At present, the significance of IGFBPs in the brain is though remain to be established, they are believed to act as inhibitory proteins limiting the availability of IGF-I to its receptors. Evidence assimilated over the last few years indicates that IGF-I, apart from stimulating cell growth, proliferation and differentiation, acts as a potent inhibitor of cell death both under in vitro and in vivo conditions (Dore et aI., 1997c). The latter effects are critical for the postmitotic neurons. It is therefore not surprising that the IGF receptors are tightly regulated and subject to rapid changes following various surgical and pharmacological manipulations (for examples, see Kar et aI., 1993; Dore et
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