Neuroprotective actions of peripherally administered insulin-like growth factor I in the injured olivo-cerebellar pathway.
Exogenous administration of insulin-like growth factor I (IGF-I) restores motor function in rats with neurotoxin-induced cerebellar deafferentation. We first determined that endogenous IGFs are directly involved in the recovery process because infusion of an IGF-I receptor antagonist into the lateral ventricle blocks gradual recovery of limb coordination that spontaneously occurs after partial deafferentation of the olivo-cerebellar circuitry. We then analysed mechanisms whereby exogenous IGF-I restores motor function in rats with complete damage of the olivo-cerebellar pathway. Treatment with IGF-I normalized several markers of cell function in the cerebellum, including calbindin, glutamate receptor 1 (GluR1), gamma-aminobutyric acid (GABA) and glutamate, which are all depressed after 3-acetylpyridine (3AP)-induced deafferentation. IGF-I also promoted functional reinnervation of the cerebellar cortex by inferior olive (IO) axons. In the IO, increased expression of bax in neurons and bcl-X in astrocytes after 3AP was significantly reduced by IGF-I treatment. On the contrary, IGF-I prevented the decrease in poly-sialic-acid neural cell adhesion molecule (PSA-NCAM) and GAP-43 expression induced by 3AP in IO cells. IGF-I also significantly increased the number of neurons expressing bcl-2 in brainstem areas surrounding the IO. Altogether, these results indicate that subcutaneous IGF-I therapy promotes functional recovery of the olivo-cerebellar pathway by acting at two sites within this circuitry: (i) by modulating death- and plasticity-related proteins in IO neurons; and (ii) by impinging on homeostatic mechanisms leading to normalization of cell function in the cerebellum. These results provide insight into the neuroprotective actions of IGF-I and may be of practical consequence in the design of new therapeutic approaches for neurodegenerative diseases.
Fernandez
A M
AM
Laboratory of Cellular and Molecular Neuroendocrinology, Cajal Institute, CSIC, Madrid, Spain.
Gonzalez de la Vega
A G
AG
Planas
B
B
Torres-Aleman
I
I
D000818:Animals; D001259:Ataxia / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects* / Q000503:physiopathology; D003714:Denervation; D006801:Humans; D007276:Injections, Intraventricular; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D009847:Olivary Nucleus / Q000187:drug effects* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013002:Somatomedins / Q000502:physiology
D018969:Insulin-Like Growth Factor Binding Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011725:Pyridines; D011994:Recombinant Proteins; D013002:Somatomedins; C010835:3-acetylpyridine; D007334:Insulin-Like Growth Factor I