The preclinical rationale for the use of insulin-like growth factor-I in 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 preclinical rationale for IGF-I use in treating patients with ALS stems from the fact that this molecule has endocrine, paracrine and autocrine effects on cells and acts through a receptor tyrosine kinase that is structurally and functionally similar to the insulin receptor. What has 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 within the peripheral and central nervous systems compared with other tissues. This signaling pathway is complex, involving several cell surface receptors, circulating and bound binding proteins and specific proteases 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) and brain-derived neurotrophic factor (BDNF), was found to have efficacy in large-scale clinical trials in ALS patients, evidence is offered that IGF-I affects all components of the motor unit: spinal cord motor neuron, axon, neuromuscular synapse and muscle fiber. A model is presented that shows life and death signals on motor neurons, with the serine protease, thrombin, representing an extracellular death signal and IGF-I, a potent life signal, on such cells.
Festoff
B W
BW
Neurobiology Research Laboratory, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri 64128, USA.