THE PRECLINICAL RATIONALE FOR THE USE OF INSULIN-LIKE GROWTH-FACTOR-IIN AMYOTROPHIC-LATERAL-SCLEROSIS

This review details the general physiology, biochemistry and molecular biology of insulin-like growth factor I (IGF-I), a pleiotropic factor , and the only one to date showing beneficial effects in a prototypic neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The pr eclinical rationale for IGF-I use in treating patients with ALS stems from the fact that this molecule has endocrine, paracrine and autocrin e effects on cells and acts through a receptor tyrosine kinase that is structurally and functionally similar to the insulin receptor. What h as come to be known as the IGF signaling system is reviewed within the context of differences as well as similarities of IGF-I's actions wit hin the peripheral and central nervous systems compared with other tis sues. This signaling pathway is complex, involving several cell surfac e receptors, circulating and bound binding proteins and specific prote ases that recognize and cleave individual binding proteins that serves to finely adjust the cellular responses to IGF-I. In order to explain why this trophic factor, unlike ciliary neurotrophic factor (CNTF) an d brain-derived neurotrophic factor (BDNF), was found to have efficacy in large-scale clinical trials in ALS patients, evidence is offered t hat IGF-I affects all components of the motor unit: spinal cord motor neuron, axon, neuromuscular synapse and muscle fiber. A model is prese nted that shows life and death signals on motor neurons, with the seri ne protease, thrombin, representing an extracellular death signal and IGF-I, a potent life signal, on such cells.