title: 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.
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.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Messi
authors.forename: Heather M
authors.initials: HM
authors.lastname: Clark
authors.forename: David M
authors.initials: DM
authors.lastname: Prevette
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Oppenheim
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Delbono
mesh_terms: D000409:Alanine; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D048429:Cell Size; D002470:Cell Survival; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005998:Glycine; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D009929:Organ Size; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D007334:Insulin-Like Growth Factor I; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000409:Alanine; D005998:Glycine