Glycosaminoglycans boost insulin-like growth factor-I-promoted neuroprotection: blockade of motor neuron death in the wobbler mouse.
Wobbler mice display forelimb weakness, altered paw positioning, reduced running speed, muscle atrophy and motor neuron loss; co-treatment with glycosaminoglycans and insulin-like growth factor-I counteracts the progression of the disease. Reportedly, treatment with glycosaminoglycans or insulin-like growth factor-I slows the early stages of progressive forelimb dysfunction in wobbler mice. Our aim was to study whether the combination of these two drugs would result in greater neuroprotective effects. In a group of wobbler mice, combined treatment with daily s.c. administration of 20 microg/kg insulin-like growth factor-I and 1 mg/kg glycosaminoglycans was begun upon diagnosis at three weeks of age and continued for the next six weeks. This treatment halted motor neuron loss and markedly reduced the decay of forelimb muscle morphometry and function. Moreover, the mouse phenotype itself was strikingly improved. The effect of the combination treatment was significantly higher than that of the single drugs, even at a dosage as high as 1 mg/kg insulin-like growth factor-I. The ability of the insulin-like growth factor-I/glycosaminoglycans pharmacological cocktail to arrest the progression of motor neuron disease in wobbler mice and the safety of the low dose of insulin-like growth factor-I used hold promise that this combination might represent a novel approach for the treatment of motor neuron disease and peripheral neuropathies.
Vergani
L
L
Department of Medical Pharmacology, University of Milan, Italy.
Losa
M
M
Lesma
E
E
Di Giulio
A M
AM
Torsello
A
A
Müller
E E
EE
Gorio
A
A
D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D006025:Glycosaminoglycans; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I