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 (ALS) 的患者会出现运动神经元变性，导致肌肉萎缩、吞咽困难和构音障碍。Wobbler 小鼠是 ALS 的一种动物模型，显示出脊髓中运动神经元、星形细胞增多症和小胶质细胞增生的选择性丢失。男性 ALS 的发病率更高；然而，它在更年期后的女性中增加，表明性类固醇在 ALS 中的作用。睾酮是一种复杂的类固醇，在芳构化为雌二醇后，直接通过雄激素 (AR) 或 Sigma-1 受体发挥作用，并通过雌激素受体 (ER) 间接发挥作用。其还原代谢物 5α-二氢睾酮通过 AR 起作用。这项研究分析了睾酮对男性有症状的摇摆者的影响。对照组或摇摆者接受空的或填充睾酮的硅橡胶管 2 个月。来自睾酮治疗的 Wobblers 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) 睾酮及其 5α-减少的代谢物、5α-二氢睾酮和 3β-雄甾烷二醇的水平升高，但 (3) 检测不到水平雌二醇与未经处理的 Wobblers 相比。睾酮处理的对照组显示出与其未处理的对应物相当的类固醇浓度。在睾酮处理的 Wobblers 中，AR、ERα 和芳香酶减少，Sigma-1 受体 mRNA 水平高。睾酮治疗增加了 ChAT 免疫反应性和抗炎介质 TGFβ，同时减少了空泡化运动神经元、GFAP+ 星形胶质细胞增生、IBA1+ 小胶质细胞增生的密度、促炎介质和氧化/亚硝化应激。临床上，Wobblers 中的睾酮治疗减缓了爪子萎缩的进展并提高了旋转棒的性能。总的来说，我们的研究结果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高浓度的雄激素减少衍生物一致，表明类固醇谱可能对疾病进展具有有益作用。