Department of Physiology and Anatomy, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas.
Endocrinology. 2019 Apr 1;160(4):947-963. doi: 10.1210/en.2018-01079.
Oxidative stress (OS) is a common characteristic of several neurodegenerative disorders, including Parkinson disease (PD). PD is more prevalent in men than in women, indicating the possible involvement of androgens. Androgens can have either neuroprotective or neurodamaging effects, depending on the presence of OS. Specifically, in an OS environment, androgens via a membrane-associated androgen receptor (mAR) exacerbate OS-induced damage. To investigate the role of androgens on OS signaling and neurodegeneration, the effects of testosterone and androgen receptor activation on the major OS signaling cascades, the reduced form of NAD phosphate (NADPH) oxidase (NOX)1 and NOX2 and the Gαq/inositol trisphosphate receptor (InsP3R), were examined. To create an OS environment, an immortalized neuronal cell line was exposed to H2O2 prior to cell-permeable/cell-impermeable androgens. Different inhibitors were used to examine the role of G proteins, mAR, InsP3R, and NOX1/2 on OS generation and cell viability. Both testosterone and DHT/3-O-carboxymethyloxime (DHT)-BSA increased H2O2-induced OS and cell death, indicating the involvement of an mAR. Furthermore, classical AR antagonists did not block testosterone's negative effects in an OS environment. Because there are no known antagonists specific for mARs, an AR protein degrader, ASC-J9, was used to block mAR action. ASC-J9 blocked testosterone's negative effects. To determine OS-related signaling mediated by mAR, this study examined NOX1, NOX2, Gαq. NOX1, NOX2, and the Gαq complex with mAR. Only NOX inhibition blocked testosterone-induced cell loss and OS. No effects of blocking either Gαq or G protein activation were observed on testosterone's negative effects. These results indicate that androgen-induced OS is via the mAR-NOX complex and not the mAR-Gαq complex.
氧化应激（OS）是几种神经退行性疾病的共同特征，包括帕金森病（PD）。PD 在男性中比女性更为普遍，这表明雄激素可能参与其中。雄激素可以具有神经保护或神经损伤作用，这取决于 OS 的存在。具体而言，在 OS 环境中，雄激素通过膜相关雄激素受体（mAR）加剧 OS 诱导的损伤。为了研究雄激素对 OS 信号和神经退行性变的作用，研究了睾酮和雄激素受体激活对主要 OS 信号级联、还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）1 和 NOX2 和 Gαq/肌醇三磷酸受体（InsP3R）的影响。为了创建 OS 环境，在细胞通透/细胞不可透的雄激素之前，将永生化神经元细胞系暴露于 H2O2 中。使用不同的抑制剂来研究 G 蛋白、mAR、InsP3R 和 NOX1/2 在 OS 产生和细胞活力中的作用。睾酮和 DHT/3-O-羧甲基肟（DHT）-BSA 均增加了 H2O2 诱导的 OS 和细胞死亡，表明 mAR 的参与。此外，经典的 AR 拮抗剂不能阻断 OS 环境中睾酮的负作用。由于没有针对 mAR 的已知拮抗剂，因此使用 AR 蛋白降解剂 ASC-J9 来阻断 mAR 作用。ASC-J9 阻断了睾酮的负作用。为了确定 mAR 介导的与 OS 相关的信号，本研究检查了 NOX1、NOX2、Gαq。NOX1、NOX2 和 mAR 的 Gαq 复合物。只有 NOX 抑制阻断了睾酮诱导的细胞丢失和 OS。阻断 Gαq 或 G 蛋白激活对睾酮的负作用没有影响。这些结果表明，雄激素诱导的 OS 是通过 mAR-NOX 复合物而不是 mAR-Gαq 复合物。
