|کد مقاله||کد نشریه||سال انتشار||مقاله انگلیسی||ترجمه فارسی||نسخه تمام متن|
|5630489||1580612||2018||14 صفحه PDF||سفارش دهید||دانلود کنید|
- Etazolate enhances the release of the neuroprotective protein sAPPÎ± from demyelinated cerebellar slices.
- Î±-Secretase-induced sAPPÎ± release rescues myelin sheaths from demyelination.
- Etazolate enhances remyelination ex vivo and in vivo.
- Beneficial effects of etazolate are blocked by an Î±-secretase inhibitor.
- sAPPÎ± protects myelin sheaths from demyelination.
Remyelination is an endogenous regenerative process of myelin repair in the central nervous system (CNS) with limited efficacy in demyelinating disorders. As strategies enhancing endogenous remyelination become a therapeutic challenge, we have focused our study on Î±-secretase-induced sAPPÎ± release, a soluble endogenous protein with neuroprotective and neurotrophic properties. However, the role of sAPPÎ± in remyelination is not known. Therefore, we investigated the remyelination potential of Î±-secretase-induced sAPPÎ± release following CNS demyelination in mice. Acute demyelination was induced by feeding mice with cuprizone (CPZ) for 5Â weeks. To test the protective effect and the remyelination potential of etazolate, an Î±-secretase activator, we designed two treatment protocols. Etazolate was administrated either during the last two weeks or at the end of the CPZ intoxication. In both protocols, etazolate restored the number of myelinated axons in corpus callosum with a corresponding increase in the amount of MBP, one of the major myelin proteins in the brain. We also performed ex vivo studies to decipher etazolate's mechanism of action in a lysolecithin-induced demyelination model using organotypic culture of cerebellar slices. Etazolate treatment was able to i) enhance the release of sAPPÎ± in the culture media of demyelinated slices, ii) protect myelinated axons from demyelination, iii) increase the number of mature oligodendrocytes, iv) promote the reappearance of the paired Caspr+ adjacent to the nodes of Ranvier and v) increase the percentage of myelinated axons with short internodes, an indicator of remyelination. Etazolate failed to promote all the aforementioned effects in the presence of GI254023X, an Î±-secretase inhibitor. Moreover, the protective effects of etazolate in demyelinated slices were mimicked by sAPPÎ± treatment in a dose-dependent manner. In conclusion, etazolate-induced sAPPÎ± release protects myelinated axons from demyelination while also promoting remyelination. This work, thus, highlights the therapeutic potential of strategies that enhance sAPPÎ± release in demyelinating disorders.
Journal: Neurobiology of Disease - Volume 109, Part A, January 2018, Pages 11-24