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Neuroprotective actions of peripherally administered insulin‐like growth factor I in the injured olivo‐cerebellar pathway
Author(s) -
Fernandez A. M.,
de la Vega A. Gonzalez,
Planas B.,
TorresAleman I.
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00623.x
Subject(s) - cerebellum , neural cell adhesion molecule , glutamate receptor , deep cerebellar nuclei , medicine , endocrinology , neuroscience , purkinje cell , chemistry , polysialic acid , insulin like growth factor , biology , cerebellar cortex , receptor , growth factor , cell , biochemistry , cell adhesion
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.