Rediscovering good old friend IGF-I in the new millenium: possible usefulness in Alzheimer's disease and stroke.

Much research has been done over the past two decades on the role of insulin-like growth factors I and II (IGF) in the maintenance of normal body homeostasis, especially in regard to various endocrine functions, growth and aging. For example, IGF-I is a well established promoter of tissue growth and has been used in the clinics for the treatment of growth related disorders, even being abused by athletes to enhance performance in competitions. In contrast, comparatively limited attention has been given to the potential significance of the IGFs in the central nervous system. Over the past few years, we have studied the trophic as well as neuromodulatory roles of the IGFs in the brain. IGF-I and IGF-II are potent modulators of acetylcholine release, IGF-I inhibiting release while IGF-II is a potent stimulant. Moreover, only the internalization of the IGF-I receptor complex was blocked by an inhibitor of phosphotyrosylation. This is in accordance with the differential nature of the IGF-I and IGF-II receptors, the former being a tyrosine kinase receptor while the later is a single transmembrane domain protein bearing binding sites for 6-mannose phosphate containing residues. The activation of IGF-I receptors protected neurons against cell death induced by amyloidogenic derivatives likely by an intracellular mechanism distinct from those involved in the regulation of acetylcholine release and neuronal growth. The stimulation of IGF-I receptors can activate intracellular pathways implicating a PI3/Akt kinase and CREB phosphorylation or modulate the production of free radicals. The effects, particularly those of IGF-I on key markers of the Alzheimer's (AD) brains namely cholinergic dysfunction, neuronal amyloid toxicity, tau phosphorylation and glucose metabolism suggest the potential usefulness of this growth factor in the treatment of neurodegenerative diseases. However, the poor bioavailability, enzymatic stability and brain penetration of IGF-I hamper progress in this regard. The recent development of a small, non-peptidyl mimetic of insulin able to directly activate the insulin receptor [Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M.T., Pelaez, F., Ruby, C., Kendall, R.L., Mao, X., Griffin, P., Calaycay, J., Zierath, J.R., Heck, J. V., Smith, R.G., Moller, D.E., 1999. Science, 284, 974-977] suggests that a similar strategy could be used for IGF-I and the IGF-I receptor leading to the characterization of IGF-I mimics of potential clinical usefulness.