Glial growth factors, proteins that are mitogenic for Schwann cells, and several ligands for the p185erbB2 receptor, are products of the same gene. Alternative splicing of the messenger RNA generates an array of putative membrane-attached, intracellular and secreted signalling proteins, at least some of which are expressed in the developing spinal cord and brain. These factors are probably important in the development and regeneration of the nervous system.

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.Most therapeutic strategies in the human demyelinating disease, multiple sclerosis (MS), have been based on modulating the immune response, and the animal model of MS, experimental autoimmune encephalomyelitis (EAE), has been particularly useful for testing potential therapeutic agents (1, 2). EAE, a CD4 ϩ T helper 1 (Th1) T cell-mediated disease of the central nervous system (CNS), involves autosensitization to myelin antigens and in the SJL mouse is a chronic relapsing neurologic disease with inflammatory demyelinated CNS lesions highly reminiscent of MS (3-5). Relatively unexplored in demyelinating conditions has been the therapeutic potential of neurotrophic factors with known regulatory effects on the myelinating cell. Prominent among these factors are members of the neuregulin family of soluble and transmembrane proteins belonging to the epidermal growth factor superfamily (6). Recombinant human glial growth factor 2 (rhGGF2) is a secreted isoform of neuregulin with documented stimulatory effects on oligodendrocytes and Schwann cells (7-10). Because oligodendrocytes are a major target in the MS lesion and because remyelination occurs in MS and EAE (3,4), it was hypothesized that administration of rhGGF2 to animals with EAE might ameliorate the disease. This report presents the findings from a large series of experiments in which rhGGF2 was given to mice at different stages of adoptively transferred chronic relapsing EAE. The results have shown that not only does rhGGF2 have marked beneficial effects at the acute and relapsing phases of the disease but it is also associated with structural and molecular evidence for enhanced remyelination of CNS lesions in long-term rhGGF2-treated animals.

The distribution of neuregulin transcripts in rat brains was studied by both RNA blotting and in situ hybridization. Our data demonstrate that multiple neuregulin transcripts are expressed in neurons of the basal forebrain, the hippocampus, the diencephalon, the cerebellum, the brainstem, and the spinal cord. Developmental changes in the distribution of neuregulin transcripts were observed only in the cerebellum and the hippocampus. The intense neuregulin hybridization signals in the brainstem motor and sensory nuclei and the spinal motor neurons are suggestive of a functional involvement of neuregulins in motor and sensory systems. The expression of neuregulins in other parts of the brain also indicates that these factors are involved in a variety of central nervous system functions.

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