Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428, Buenos Aires, Argentina.
U1195 Inserm and University Paris-Sud and University Paris-Saclay, 80 rue du Général Leclerc, Le Kremlin-Bicêtre, 94276, France.
Mol Neurobiol. 2021 May;58(5):2088-2106. doi: 10.1007/s12035-020-02209-5. Epub 2021 Jan 7.
Patients suffering of amyotrophic lateral sclerosis (ALS) present motoneuron degeneration leading to muscle atrophy, dysphagia, and dysarthria. The Wobbler mouse, an animal model of ALS, shows a selective loss of motoneurons, astrocytosis, and microgliosis in the spinal cord. The incidence of ALS is greater in men; however, it increases in women after menopause, suggesting a role of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR) or Sigma-1 receptors and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5α-dihydrotestosterone acts via AR. This study analyzed the effects of testosterone in male symptomatic Wobblers. Controls or Wobblers received empty or testosterone-filled silastic tubes for 2 months. The cervical spinal cord from testosterone-treated Wobblers showed (1) similar androgen levels to untreated control and (2) increased levels of testosterone, and its 5α-reduced metabolites, 5α- dihydrotestosterone, and 3β-androstanediol, but (3) undetectable levels of estradiol compared to untreated Wobblers. Testosterone-treated controls showed comparable steroid concentrations to its untreated counterpart. In testosterone- treated Wobblers a reduction of AR, ERα, and aromatase and high levels of Sigma-1 receptor mRNAs was demonstrated. Testosterone treatment increased ChAT immunoreactivity and the antiinflammatory mediator TGFβ, while it lessened vacuolated motoneurons, GFAP+ astrogliosis, the density of IBA1+ microgliosis, proinflammatory mediators, and oxidative/nitrosative stress. Clinically, testosterone treatment in Wobblers slowed the progression of paw atrophy and improved rotarod performance. Collectively, our findings indicate an antiinflammatory and protective effect of testosterone in the degenerating spinal cord. These results coincided with a high concentration of androgen-reduced derivatives after testosterone treatment suggesting that the steroid profile may have a beneficial role on disease progression.
患有肌萎缩侧索硬化症（ALS）的患者表现出运动神经元退化，导致肌肉萎缩、吞咽困难和构音障碍。Wobbler 小鼠是 ALS 的动物模型，其脊髓中表现出运动神经元选择性丧失、星形胶质细胞增生和小胶质细胞增生。ALS 的发病率在男性中较高；然而，女性在绝经后发病率增加，表明性激素在 ALS 中起作用。睾酮是一种复杂的类固醇，可通过雄激素（AR）或 Sigma-1 受体直接发挥作用，并在芳香化为雌二醇后通过雌激素受体（ER）间接发挥作用。其还原代谢物 5α-二氢睾酮通过 AR 起作用。本研究分析了睾酮对雄性症状性 Wobbler 的影响。对照组或 Wobbler 接受空或充满睾酮的硅橡胶管治疗 2 个月。经睾酮治疗的 Wobbler 的颈脊髓显示（1）与未治疗的对照组相似的雄激素水平和（2）增加的睾酮及其 5α-还原代谢物 5α-二氢睾酮和 3β-雄烷二醇水平，但（3）与未治疗的 Wobbler 相比，无法检测到雌二醇水平。经睾酮治疗的对照组表现出与其未治疗对照物相当的类固醇浓度。在经睾酮治疗的 Wobbler 中，AR、ERα 和芳香酶的表达减少，Sigma-1 受体 mRNA 的水平升高。睾酮治疗增加了 ChAT 免疫反应性和抗炎介质 TGFβ，同时减少了空泡运动神经元、GFAP+星形胶质细胞增生、IBA1+小胶质细胞增生密度、促炎介质和氧化/硝化应激。临床上，Wobbler 中的睾酮治疗减缓了爪萎缩的进展并改善了旋转棒性能。总的来说，我们的发现表明睾酮在退化的脊髓中具有抗炎和保护作用。这些结果与睾酮治疗后雄激素还原衍生物浓度升高相一致，表明类固醇谱可能对疾病进展具有有益作用。
