Neuroprotective actions of peripherally administered insulin-like growth factor I in the injured olive-cerebellar pathway

Exogenous administration of insulin-like growth factor I (IGF-I) restores m otor function in rats with neurotoxin-induced cerebellar deafferentation. W e first determined that endogenous IGFs are directly involved in the recove ry process because infusion of an IGF-I receptor antagonist into the latera l ventricle blocks gradual recovery of limb coordination that spontaneously occurs after partial deafferentation of the olive-cerebellar circuitry. We then analysed mechanisms whereby exogenous IGF-I restores motor function i n rats with complete damage of the olive-cerebellar pathway. Treatment with IGF-I normalized several markers of cell function in the cerebellum, inclu ding calbindin, glutamate receptor I (GluR1), gamma-aminobutyric acid (GABA ) and glutamate, which are all depressed after 3-acetylpyridine (3AP)-induc ed deafferentation. IGF-I also promoted functional reinnervation of the cer ebellar cortex by inferior olive (IO) axons. In the IO, increased expressio n of bar in neurons and bcl-X in astrocytes after 3AP was significantly red uced by IGF-I treatment. On the contrary, IGF-I prevented the decrease in p oly-sialic-acid neural cell adhesion molecule (PSA-NCAM) and GAP-43 express ion induced by 3AP in IO cells. IGF-I also significantly increased the numb er of neurons expressing bcl-2 in brainstem areas surrounding the IO, Altog ether, these results indicate that subcutaneous IGF-I therapy promotes func tional recovery of the olive-cerebellar pathway by acting at two sites with in 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 ins ight into the neuroprotective actions of IGF-I and may be of practical cons equence in the design of new therapeutic approaches for neurodegenerative d iseases.