Steroid hormones and neurosteroids in normal and pathological aging of the nervous system
Steroid hormones and neurosteroids in normal and pathological aging of the nervous system
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DOI：
10.1016/j.pneurobio.2003.09.004
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发表时间：
2003-09
影响因子：
6.7
通讯作者：
M. Schumacher;S. Weill‐Engerer;P. Liere;F. Robert;R. Franklin;L. Garcia-Segura;J. Lambert;W. Mayo;R. Melcangi;Á. Párducz;U. Suter;C. Carelli;E. Baulieu;Y. Akwa
中科院分区：
文献类型：
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作者：
M. Schumacher;S. Weill‐Engerer;P. Liere;F. Robert;R. Franklin;L. Garcia-Segura;J. Lambert;W. Mayo;R. Melcangi;Á. Párducz;U. Suter;C. Carelli;E. Baulieu;Y. Akwa
如果医学没有进步，阿尔茨海默病等痴呆症将成为致残的主要原因之一。因此，预防或延缓这些疾病已成为生物医学研究的真正挑战。类固醇在促进成功衰老方面提供了有趣的治疗机会，因为它们在神经系统中具有多效性：它们调节主要的神经递质系统，促进神经元的活力，在髓鞘形成中发挥重要作用，并影响认知过程，特别是学习和记忆。临床前研究提供的证据表明，正常衰老的神经系统仍有一定的再生能力，神经系统的年龄依赖性变化和认知功能障碍可以通过类固醇治疗在一定程度上得到逆转。老化的神经系统也对类固醇的神经保护作用保持敏感。与大量记录类固醇对幼龄和老年动物的神经系统有益作用的研究相反，对老年人进行激素替代研究的结果迄今尚无定论。关于衰老人类大脑中类固醇水平变化的信息也很少。由于存在于神经组织中的类固醇来源于内分泌腺（类固醇激素）和局部合成（神经类固醇），血液中类固醇水平随年龄的变化并不一定反映大脑中类固醇水平的变化。确实有强有力的证据表明，神经类固醇也在人脑和周围神经中合成。气相色谱/质谱联用技术（GC/MS）的发展为神经甾体的研究提供了新的可能性。最近用GC/MS测量了老年阿尔茨海默病患者和老年非痴呆对照者不同脑区一系列神经类固醇的浓度，提供了参考值。在阿尔茨海默病患者中，大脑不同区域的神经类固醇水平普遍呈降低趋势，神经类固醇水平与阿尔茨海默病的两种生化标志物——磷酸化的tau蛋白和β-淀粉样肽呈负相关。脱氢表雄酮的代谢也首次在老年痴呆症患者和非痴呆对照组的衰老大脑中进行了分析。阿尔茨海默病患者和对照组的额叶皮质、海马、杏仁核、小脑和纹状体均发生脱氢表雄酮向Δ5-androstene-3β、17β-二醇和7α- oh -脱氢表雄酮的转化。这些代谢物在大脑不同区域的形成与β-淀粉样蛋白沉积的密度呈负相关。
Without medical progress, dementing diseases such as Alzheimer’s disease will become one of the main causes of disability. Preventing or delaying them has thus become a real challenge for biomedical research. Steroids offer interesting therapeutical opportunities for promoting successful aging because of their pleiotropic effects in the nervous system: they regulate main neurotransmitter systems, promote the viability of neurons, play an important role in myelination and influence cognitive processes, in particular learning and memory. Preclinical research has provided evidence that the normally aging nervous system maintains some capacity for regeneration and that age-dependent changes in the nervous system and cognitive dysfunctions can be reversed to some extent by the administration of steroids. The aging nervous system also remains sensitive to the neuroprotective effects of steroids. In contrast to the large number of studies documenting beneficial effects of steroids on the nervous system in young and aged animals, the results from hormone replacement studies in the elderly are so far not conclusive. There is also little information concerning changes of steroid levels in the aging human brain. As steroids present in nervous tissues originate from the endocrine glands (steroid hormones) and from local synthesis (neurosteroids), changes in blood levels of steroids with age do not necessarily reflect changes in their brain levels. There is indeed strong evidence that neurosteroids are also synthesized in human brain and peripheral nerves. The development of a very sensitive and precise method for the analysis of steroids by gas chromatography/mass spectrometry (GC/MS) offers new possibilities for the study of neurosteroids. The concentrations of a range of neurosteroids have recently been measured in various brain regions of aged Alzheimer’s disease patients and aged non-demented controls by GC/MS, providing reference values. In Alzheimer’s patients, there was a general trend toward lower levels of neurosteroids in different brain regions, and neurosteroid levels were negatively correlated with two biochemical markers of Alzheimer’s disease, the phosphorylated tau protein and the β-amyloid peptides. The metabolism of dehydroepiandrosterone has also been analyzed for the first time in the aging brain from Alzheimer patients and non-demented controls. The conversion of dehydroepiandrosterone to Δ5-androstene-3β,17β-diol and to 7α-OH-dehydroepiandrosterone occurred in frontal cortex, hippocampus, amygdala, cerebellum and striatum of both Alzheimer’s patients and controls. The formation of these metabolites within distinct brain regions negatively correlated with the density of β-amyloid deposits.