The Lack of Effect of Specific Overexpression of IGF-1 in the Central Nervous System or Skeletal Muscle on Pathophysiology in the G93A SOD-1 Mouse Model of ALS

Exp Neurol. 2007 Sep;207(1):52-63. doi: 10.1016/j.expneurol.2007.05.016. Epub 2007 Jun 2.

Abstract

The ability of insulin like growth factor 1 (IGF-1) to prevent the pathophysiology associated with amyotrophic lateral sclerosis (ALS) is currently being explored with animal models and in clinical trials with patients. Several studies have reported positive effects of IGF-1 in reducing motor neuron death, delaying the onset of motor performance decline, and increasing life span, in SOD-1 mouse models of ALS and in one clinical trial. However, a second clinical trial produced no positive results raising questions about the therapeutic efficacy of IGF-1. To investigate the effect of specific and sustained IGF-1 expression in skeletal muscle or central nervous system on motor performance, life span, and motor neuron survival, human-IGF-1 transgenic mice were crossed with the G93A SOD-1 mutant model of ALS. No significant differences were found in onset of motor performance decline, life span, or motor neuron survival in the spinal cord, between SOD+/IGF-1+ and SOD+/IGF-1- hybrid mice. IGF-1 concentration levels, measured by radioimmunoassay, were found to be highly increased throughout life in the central nervous system (CNS) and skeletal muscle of IGF-1 transgenic hybrid mice. Additionally, increased CNS weight in SOD+ mice crossbred with CNS IGF-1 transgenic mice demonstrates that IGF-1 overexpression is biologically active even after the disease is fully developed. Taken together, these results raise questions concerning the therapeutic value of IGF-1 and indicate that further studies are needed to examine the relationship between methods of IGF-1 administration and its potential therapeutic value.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Cell Size
  • Cell Survival
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Central Nervous System / physiopathology
  • Glycine
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Longevity
  • Mice
  • Mice, Transgenic
  • Motor Activity
  • Motor Neurons / pathology
  • Muscle, Skeletal / metabolism*
  • Mutation*
  • Organ Size
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1

Substances

  • SOD1 protein, human
  • Insulin-Like Growth Factor I
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Alanine
  • Glycine