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Neuroprotective actions of peripherally administered insulin‐like growth factor I in the injured olivo‐cerebellar pathway

Neuroprotective actions of peripherally administered insulin‐like growth factor I in the injured... 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), γ‐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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Neuroscience Wiley

Neuroprotective actions of peripherally administered insulin‐like growth factor I in the injured olivo‐cerebellar pathway

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References (60)

Publisher
Wiley
Copyright
Copyright © 1999 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0953-816X
eISSN
1460-9568
DOI
10.1046/j.1460-9568.1999.00623.x
Publisher site
See Article on Publisher Site

Abstract

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), γ‐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.

Journal

European Journal of NeuroscienceWiley

Published: Jun 1, 1999

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