Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination.

Abstract

To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone [bis (cyclohexanone) oxaldihydrazone]. This copper-chelating agent produces demyelination in the corpus callosum and superior cerebellar peduncles, and when treatment is stopped, there is rapid remyelination. At intervals during cuprizone treatment and recovery, brain sections were hybridized with specific probes and immunostained with antibodies to determine the localization and relative amounts of IGF-I and IGF-I receptor mRNAs and peptides. In untreated littermates, IGF-I and IGF-I receptor mRNAs and peptides were not detected in white matter. In cuprizone-treated mice, high levels of both IGF-I mRNA and peptide were expressed by astrocytes in areas of myelin breakdown. Astrocyte IGF-I expression decreased rapidly during recovery and oligodendroglial expression of myelin-related genes increased. In se- Insulin-like growth factor I (IGF-I), a member of the insulin gene family (1,2), has been shown to have a number ofpotent effects on cultured neural and glial cells. It promotes the mitosis of sympathetic neuroblasts, the survival of fetal neurons, and the stimulation of neurite outgrowth in motor and sensory neurons, and it induces oligodendrocyte differentiation and myelin synthesis (3-10). These effects are mediated by the type I IGF receptor, which is a membranebound tyrosine kinase with significant homology to the insulin receptor (11, 12). IGF-I gene expression is abundant in the developing nervous system (13-18). IGF-I mRNA is selectively concentrated in the large principal neurons of functionally related sensory and cerebellar relay systems during a late predominantly postnatal phase of neural development (18). The specific timing and cellular sites of neural IGF-I synthesis suggest a role for IGF-I in the synaptic maturation or the myelination of these particular systems. Evidence that IGF-I has a role in myelination is the finding that transgenic mice overexpressing IGF-I (19) have increased brain myelin content (20). Also, several studies have shown that IGFs have potent and highly specific effects on oligodendrocytes in vitro (7-10). However, except for the olfactory system, very little IGF-I is normally detected in the mature rodent brain (16-18).To investigate whether IGF-I is important in the regeneration of central nervous system myelin in vivo, demyelinating lesions were produced in the corpus callosum, superior cerebellar peduncles, and anterior commissures by adding the copper-chelating agent bis(cyclohexanone) oxaldihydrazone (cuprizone) to the diet of mice (21-23). In this model of primary demyelination, there are early severe changes in oligodendroglia and myelin sheaths in specific brain areas (21-23). Axons are relatively well preserved (21-23) and the blood-brain barrier remains impermeable to plasma proteins (24). There are no perivascular lymphocytic infiltrates (21,22) and the cessation of cuprizone tr...

Astrogliosis in the Neonatal and Adult Murine Brain Post-Trauma: Elevation of Inflammatory Cytokines and the Lack of Requirement for Endogenous Interferon-γ

“…Neurotrophic factors are produced around the locus of CNS lesions, and although earlier studies did not identify the source of these factors (NietoSampedro et al, 1982(NietoSampedro et al, , 1983Needels et al, 1986;Ernfors et al, 1989;Ishikawa et al, 1991;Lindvall et al, 1994), more recent studies have documented the upregulation of nerve growth factor (NGF) (Bakhit et al, 1991;Altar et al, 1992;Oderfeld-Nowak et al, 1992;Arendt et al, 1995), ciliary neurotrophic factor (Ip et al, 1993;Asada et al, 1995;Wen et al, 1995), basic fibroblast growth factor (Finklestein et al, 1988;Frautschy et al, 1991;GomezPinilla et al, 1995;Wen et al, 1995), and insulin-like growth factor-1 (Komoly et al, 1992) in reactive astrocytes.…”

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“…It is recognized, for instance, that IGF-1 and -2 stimulate the proliferation of these cells (30) and receptors for IGF-1 are expressed in astrocytes and oligodendrocytes present on the edges of demyelinating lesions (31).…”

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

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