Co-administration of IGF-I and glycosaminoglycans greatly delays motor neurone disease and affects IGF-I expression in the wobbler mouse: a long-term study.
The study on wobbler mouse has shown that the combined treatment with low doses of glycosaminoglycans (GAGs) and insulin-like growth factor-I (IGF-I) fully prevented motor neurone death and forelimb impairment up to 9-12 weeks of a mouse's life. The effect was accompanied by the prevention of the early hypertrophy of wobbler neurones, an effect likely due to the promotion of neuronal survival. At the 18th week, wobbler mice treated with IGF-I + GAGs still showed significantly improved forelimb function, reduced muscle atrophy and a higher number of cervical motor neurones. IGF-I alone and GAGs alone were active up to the 3rd week of treatment; thereafter the beneficial effects of single treatments decreased drastically. GAGs and IGF-I treatments also affected IGF-I plasma and muscle levels. In wobbler mice there was a progressive reduction in IGF-I plasma levels that was prevented by IGF-I or GAGs alone and greatly increased, even above heterozygote levels, by the combination treatment. Such a powerful increase was correlated by a small enhancement in insulin-like growth factor binding protein-3 (IGFBP-3) plasma levels, while treatment with IGF-I alone affected very significantly both IGFBP-1 and IGFBP-3. Co-treatment also prevented the decrease in IGF-I content observed in vehicle-treated wobbler mice forelimb muscles.
Gorio
Alfredo
A
Department of Medicine, Polo H San Paolo, Faculty of Medicine, Milano, Italy. Alfredo.Gorio@unimi.it
Lesma
Elena
E
Madaschi
Laura
L
Di Giulio
Anna Maria
AM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005552:Forelimb / Q000294:innervation / Q000503:physiopathology; D006025:Glycosaminoglycans / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D013995:Time
D006025:Glycosaminoglycans; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I