Long-term neuroprotective effects of glycosaminoglycans-IGF-I cotreatment in the motor neuron degeneration (mnd) mutant mouse.
This study shows that cotreatment with insulin-like growth factor-I (IGF-I) and glycosaminoglycans (GAGs) prevents the onset of neuromuscular deficit in the m/m mutant mouse. These mice show a mid-to-late-life onset of progressive paralysis of the hind limb, that is correlated with altered innervation and reduced nerve-evoked isometric twitch tension in the extensor digitorum longus (EDL) muscle. Almost 50% of EDL nerve endings are negative for antisynaptophysin staining, while retrograde labelling with beta-cholera-toxin coupled to type IV horseradish and quantitative histological analysis show a small loss of EDL and lumbar cord motor neurons. At 10 months of age also forelimb function evaluated as grip strength is significantly reduced. Animals treated either with glycosaminoglycans alone or with IGF-I alone at low and high doses showed only a partial improvement of their condition. However, cotreatment of m/m mice with IGF-I and GAGs fully prevented the neuromuscular abnormalities, the twitch tension loss, the motor neuron decrease and the reduction of forelimb grip strength.
Gorio
A
A
Laboratory for Research on Pharmacology of Neurodegenerative Disorders, Department of Pharmacology, Chemotherapy and Medical Toxicology, Milano, Italy. algorio@imiucca.csi.unimi.it
Germani
E
E
Lesma
E
E
Rossoni
G
G
Muller
E E
EE
Di Giulio
A M
AM
D000818:Animals; D001284:Atrophy; D002452:Cell Count; D002772:Cholera Toxin; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005456:Fluorescent Dyes; D006497:Heparan Sulfate / Q000494:pharmacology*; D006735:Horseradish Peroxidase; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics; D009468:Neuromuscular Diseases / Q000188:drug therapy / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000737:chemistry; D012235:Rhodamines; D016708:Synaptophysin / Q000032:analysis / Q000276:immunology
D002772:Cholera Toxin; D003871:Dermatan Sulfate; D005456:Fluorescent Dyes; D006497:Heparan Sulfate; D006735:Horseradish Peroxidase; D007334:Insulin-Like Growth Factor I; D018696:Neuroprotective Agents; D012235:Rhodamines; D016708:Synaptophysin; C052635:cholera toxin, B subunit-horseradish peroxidase; C029773:rhodamine B