Chronic disabilities in multiple sclerosis are believed to be due to neuron damage and degeneration, which follow remyelination failure. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, one reason for demyelination failure could be the inability of oligodendrocyte precursor cells to turn into myelinating oligodendrocytes. In this study, we show that thyroid hormone enhances and accelerates remyelination in an experimental model of chronic demyelination, i.e., experimental allergic encephalomyelitis in congenic female Dark Agouti rats immunized with complete guinea pig spinal cord. Thyroid hormone, when administered during the acute phase of the disease, increases expression of platelet-derived growth factor ␣ receptor, restores normal levels of myelin basic protein mRNA and protein, and allows an early and morphologically competent reassembly of myelin sheaths. Moreover, thyroid hormone exerts a neuroprotective effect with respect to axonal pathology.neuroprotection ͉ multiple sclerosis ͉ oligodendrocyte precursor cells ͉ axonal pathology ͉ rat M ultiple sclerosis (MS) is a disorder of the central nervous system (CNS) that manifests as acute focal inflammatory demyelination with limited remyelination, usually culminating in chronic multifocal sclerotic plaques (1). Early axonal injury and loss followed by neuron distress (2) and death (3) occur in MS (4-6), accounting for brain and spinal cord atrophy. Irreversible axonal damage is an essential cause of nonremitting sensory, motor, and cognitive disabilities in MS (7). Although remyelination occurs in most experimental models of demyelination, this beneficial process is undoubtedly inadequate in MS. The reasons for this inadequacy are unknown, also because the oligodendrocyte precursor cells (OPCs), the cell population that is considered to be the most important source of remyelinating oligodendrocytes in the adult CNS (8-10), are present in early (fresh) demyelinating lesions in MS (11, 12).There are many possible speculative explanations for remyelination failure in MS (9, 10), including quantitatively inadequate recruitment and͞or differentiation of OPCs (13); axons not receptive to remyelination (14); and inappropriate support of growth factors by astrocytes and͞or other inflammatory cells (15), such as the extracellular microenvironment with regard to matrix proteins and adhesion molecules (16).Because the number of oligodendrocytes is greater than before demyelination in early MS, meaning that new oligodendrocytes are generated (17), another possibility is that OPCs are unable to turn into myelinating oligodendrocytes in chronic MS. Thus, extensive studies are under way to identify factors involved in OPC differentiation during remyelination. It is generally accepted that the process of remyelination represents a recapitulation of myelination during development, and so the key factors affecting the developmental maturation of OPCs into myelinating oligodendrocytes also should favor remyelination in the adult CNS. It ...

Degenerative diseases represent a severe problem because of the very limited repair capability of the nervous system. To test the potential of using stem cells in the adult central nervous system as ''brain-marrow'' for repair purposes, several issues need to be clarified. We are exploring the possibility of influencing, in vivo, proliferation, migration, and phenotype lineage of stem cells in the brain of adult animals with selective neural lesions by exogenous administration (alone or in combination) of hormones, cytokines, and neurotrophins. Lesion of the cholinergic system in the basal forebrain was induced in rats by the immunotoxin 192 IgG-saporin. Alzet osmotic minipumps for chronic release (over a period of 14 days) of mitogens [epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF)] were implanted in animals with behavioral and biochemical cholinergic defect and connected to an intracerebroventricular catheter. After 14 days of delivery, these pumps were replaced by others delivering nerve growth factor (NGF) for an additional 14 days. At the same time, retinoic acid was added to the rats' food pellets for one month. Whereas the lesion decreased proliferative activity, EGF and bFGF both increased the number of proliferating cells in the subventricular zone in lesioned and nonlesioned animals. These results are indicated by the widespread distribution of BrdUrd-positive nuclei in the forebrain, including in the cholinergic area. Performance in the water maze test was improved in these animals and choline acetyltransferase activity in the hippocampus was increased. These results suggest that pharmacological control of endogenous neural stem cells can provide an additional opportunity for brain repair. These studies also offer useful information for improving integration of transplanted cells into the mature brain.

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Galanin is a neuropeptide involved in a variety of biological functions, including having a strong anticonvulsant activity. To assess a possible role of galanin in modulation of glutamatergic synapses and excitotoxicity, we studied effects of a galanin receptor 2(3) agonist (AR-M1896) on several molecular events induced by glutamate administration in primary neural hippocampal cells. Exposure of cells, after 5 days in vitro, to glutamate 0.5 mM for 10 min caused morphological alterations, including disaggregation of b-tubulin and MAP-2 cytoskeletal protein assembly, loss of neurites and cell shrinkage. When present in culture medium together with glutamate, 1 and 10 nM of AR-M1896 reduced these alterations. Moreover, AR-M1896 counteracted glutamate-induced c-fos mRNA and c-Fos protein up-regulation after 30-150 min, and 24 h, respectively. Massive nuclear alterations (Hoechst 33258 staining), observed 24 h after glutamate exposure, were also antagonized by AR-M1896 (0.1-100 nM) in a dose-dependent manner. These findings indicate that galanin, probably mainly through its type 2 receptor, interferes with events associated with glutamate toxicity.