Brain:雄激素或可治疗神经脱髓鞘病

2013-02-01 Brain 新华网

  法美研究人员在最新一期英国学术期刊《脑》上报告说,他们发现睾丸酮等雄激素能刺激髓鞘再生,有望用来治疗多发性硬化症等神经脱髓鞘病。   髓鞘是包裹在神经细胞轴突外的一层膜,具有保护轴突并提高神经冲动传导速度的作用。脱髓鞘病是由髓鞘形成障碍或其受到破坏导致的一种神经疾病,目前尚无有效方法能够刺激髓鞘修复。   法国和美国的研究人员发现,髓鞘脱失的实验鼠经过6至9个星期的睾丸酮治疗后,其神经细胞

  法美研究人员在最新一期英国学术期刊《脑》上报告说,他们发现睾丸酮等雄激素能刺激髓鞘再生,有望用来治疗多发性硬化症等神经脱髓鞘病。

  髓鞘是包裹在神经细胞轴突外的一层膜,具有保护轴突并提高神经冲动传导速度的作用。脱髓鞘病是由髓鞘形成障碍或其受到破坏导致的一种神经疾病,目前尚无有效方法能够刺激髓鞘修复。

  法国和美国的研究人员发现,髓鞘脱失的实验鼠经过6至9个星期的睾丸酮治疗后,其神经细胞轴突外的髓鞘得以再生,脱髓鞘病症状显著减轻。但中枢神经系统中雄激素受体缺失的实验鼠即使接受雄激素治疗,其髓鞘也不会再生。

  研究人员解释说,睾丸酮及与其相似的雄激素能诱导神经干细胞分化成少突胶质细胞,再由少突胶质细胞形成髓鞘并包围神经细胞轴突。

  研究人员认为,这一成果不仅有助于开发脱髓鞘病治疗方法,还表明血液中睾丸酮含量或可被当作衡量脱髓鞘病程度的生化指标。


The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination
Summary
Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.    

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