Steroid Profiling in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis
Steroid Profiling in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis
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DOI：
10.1210/en.2016-1244
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发表时间：
2016-11-01
期刊：
影响因子：
4.8
通讯作者：
Guennoun, Rachida
中科院分区：
文献类型：
--
作者：
Deniselle, Maria Claudia Gonzalez;Liere, Philippe;Guennoun, Rachida
Wobbler小鼠是人类运动神经元疾病，特别是肌萎缩性侧索硬化症（ALS）的动物模型，用于病理和治疗研究。ALS是一种致命的神经退行性疾病，其特征是运动神经元的选择性和进行性死亡，导致进行性瘫痪。先前有限的研究报道了Wobbler小鼠和ALS患者的类固醇激素失调，提示内分泌功能障碍可能参与疾病的发病机制。在这项研究中，我们用气相色谱联用质谱法建立了2个月大的雄性Wobbler小鼠及其窝鼠的大脑、脊髓、血浆、肾上腺和睾丸的类固醇谱。我们的研究结果显示：1)在Wobbler小鼠中肾上腺、血浆、脊髓区域（颈椎、胸椎、腰椎）和大脑的皮质酮水平显著上调；2)睾丸、血浆、脊髓和大脑中的T水平明显下降；3)孕酮水平升高，尤其是其代谢物α -二氢孕酮、异孕酮和α -二氢孕酮在脑、脊髓和肾上腺中的含量降低。此外，Wobbler小鼠表现出下丘脑-垂体-性腺功能低下。有趣的是，在对照组和Wobbler小鼠中，血浆皮质酮和T的浓度与它们各自在颈脊髓中的水平密切相关。T的下调可能是肾上腺亢进的结果，孕酮及其减少的代谢物的上调可能对应于运动神经元退行性变的内源性保护机制。我们的研究结果表明，血浆中皮质酮水平升高和T水平降低可能是运动神经元变性的标志。
The Wobbler mouse is an animal model for human motoneuron diseases, especially amyotrophic lateral sclerosis (ALS), used in the investigation of both pathology and therapeutic treatment. ALS is a fatal neurodegenerative disease, characterized by the selective and progressive death of motoneurons, leading to progressive paralysis. Previous limited studies have reported steroidal hormone dysregulation in Wobbler mouse and in ALS patients, suggesting endocrine dysfunctions which may be involved in the pathogenesis of the disease. In this study, we established a steroid profiling in brain, spinal cord, plasma, adrenal glands, and testes in 2-month-old male Wobbler mice and their littermates by gas chromatography coupled to mass spectrometry. Our results show in Wobbler mice the following: 1) a marked up-regulation of corticosterone levels in adrenal glands, plasma, spinal cord regions (cervical, thoracic, lumbar) and brain; 2) a strong decrease in T levels in the testis, plasma, spinal cord, and brain; and 3) increased levels of progesterone and especially of its reduced metabolites 5 alpha-dihydroprogesterone, allopregnanolone, and 20 alpha-dihydroprogesterone in the brain, spinal cord, and adrenal glands. Furthermore, Wobbler mice showed a hypothalamic-pituitary-gonadal hypoactivity. Interestingly, plasma concentrations of corticosterone and T correlate well with their respective levels in cervical spinal cord in both control and Wobbler mice. T down-regulation is probably the consequence of adrenal hyperactivity, and the up-regulation of progesterone and its reduced metabolites may correspond to an endogenous protective mechanism in response to motoneuron degeneration. Our findings suggest that increased levels of corticosterone and decreased levels of T in plasma could be a signature of motoneuron degeneration.