Steroids and the reversal of age-associated changes in myelination and remyelination.

The myelin sheaths that surround all but the smallest diameter axons within the mammalian central nervous system (CNS) must maintain their structural integrity for many years. Like many tissues, however, this function is prone to the effects of ageing, and various structural anomalies become apparent in the aged CNS. Similarly, the regenerative process by which myelin sheaths, lost as a consequence of exposure to a demyelinating insult, are restored (remyelination) is also affected by age. As animals grow older, the efficiency of remyelination progressively declines. In this article, we review both phenomena and describe how both can be partially reversed by steroid hormones and their derivatives.

The re-expression of the homeodomain transcription factor Gtx during remyelination of experimentally induced demyelinating lesions in young and old rat brain.

Since myelination and remyelination both involve investing an axon with a myelin sheath, a plausible hypothesis is that the two processes involve the expression of similar transcription factors. In this study we have addressed this hypothesis by comparing the expression of messenger RNA of Gtx, a homeodomain transcription factor expressed within oligodendrocytes during myelination, with the expression of messenger RNAs of the major myelin proteins, myelin basic protein and proteolipid protein during remyelination of experimentally induced demyelination in the adult rat brain. We have found a close temporal and spatial association between the expression patterns of the three messenger RNA species during remyelination. By comparing the expression patterns in rapidly remyelinating lesions in young adult rats with slowly remyelinating lesions in old adult rats, we have shown that Gtx messenger RNA expression follows the reappearance of myelin basic protein and proteolipid protein messenger RNAs regardless of the rate of remyelination. This observation demonstrates a clear association between the expression of Gtx messenger RNA and myelin repair. We have also shown that there is a decrease in constitutive levels of expression of myelin basic protein, proteolipid protein and Gtx messenger RNA in old adults compared with young adults. Taken together, our results indicate that Gtx, which has multiple binding sites in the promoter regions of both myelin basic protein and proteolipid protein genes, may have a similar role in the regulation of myelin protein gene expression during remyelination as has been proposed in myelination.

SCIP/Oct-6, Krox-20, and desert hedgehog mRNA expression during CNS remyelination by transplanted olfactory ensheathing cells.

Olfactory ensheathing cells (OECs), although having a separate developmental origin to Schwann cells, are able to generate myelin sheaths following transplantation into areas of CNS demyelination that are remarkably similar to those made by Schwann cells. The transcriptional control of Schwann cell myelination has been well documented, in particular the role of SCIP/Oct-6 and Krox-20. It is not known, however, whether these transcription factors are also expressed when OECs assume a myelinating phenotype. In this study, we addressed this question by using a transplantation approach to generate myelinating OECs and then examined the expression of SCIP/Oct-6 and Krox-20 mRNA by in situ hybridization using oligonucleotide probes. We also examined the expression of desert hedgehog (Dhh), a Schwann cell-derived signaling molecule that is responsible for regulating the development of the connective tissue elements in peripheral nerve, which bear similarities to the morphologies adopted by nonmyelinating transplanted cells. Our results indicate that both Krox-20 and Dhh mRNA are strongly expressed by transplanted OECs, with SCIP mRNA present at much lower levels. The expression of Krox-20 relative to the expression of P0 mRNA by the transplanted OECs is consistent with its playing a similar role in OEC myelination to that in Schwann cell myelination, while the expression of Dhh suggests a possible mechanism for the diverse morphologies that cells adopt following OEC transplantation into the damaged CNS. Taken together, our results provide further evidence for the close similarity of OECs and Schwann cells and suggest that, despite their separate origins, the manner in which they generate a peripheral-type myelin sheath involves similar regulatory mechanisms.

Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination.

An association between macrophages and remyelination efficiency has been observed in a variety of different models of CNS demyelination. In order to test whether this association is causal or coincidental, we have examined the effects of macrophage depletion on the rate of remyelination of lysolecithin-induced demyelination in the spinal cord of young adult female rats. Macrophage depletion was achieved by reducing the monocyte contribution to the macrophages within the lesion using the clodronate-liposome technique. This technique not only resulted in a decrease in Ox-42-positive cells in the spleen of treated animals but also in the levels of macrophage scavenger receptor type B mRNA expression within the demyelinating lesion. In animals treated with clodronate-liposomes throughout the remyelination process, there was a significant decrease in the extent of oligodendrocyte remyelination at 3 weeks after lesion induction, but no effect on Schwann cell remyelination. If macrophage depletion was delayed until the second half of the remyelination phase, then there was no effect on the repair outcome, implying that macrophages are required for the early stages of CNS remyelination. The results of this study indicate that the macrophage response is an important component of successful CNS remyelination and that approaches to the treatment of demyelinating disease based on inhibition of the inflammatory response may also impair regenerative events that follow demyelination.