Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Department of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005. Epub 2013 Dec 12.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Recently, it has been reported that a mutation in the sigma-1 receptor causes juvenile ALS. Therefore, the function of the sigma-1 receptor may be important in the pathology of ALS. In the present study, we investigated the effect of SA4503, a sigma-1 receptor agonist, against in in vitro and in vivo ALS models. We first investigated whether SA4503, a sigma-1 receptor agonist, prevented superoxide dismutase 1 (SOD1(G93A))- and serum free-induced cell death of mice motor neuron cells (NSC34) in in vitro model of an ALS. At concentrations of 1-10μM, SA4503 reduced SOD1(G93A)-induced cell death in a concentration-dependent manner, and BD1047, a sigma-1 receptor antagonist, inhibited the protective effect of SA4503. Next, we investigated whether SA4503 affected the phosphorylation levels of Akt (Ser 473) and extracellular signal-regulated kinase (ERK) 1/2 and the expression of the sigma-1 receptor. SA4503 promoted the phosphorylation of Akt (Ser 473) and ERK1/2 in a time-dependent manner, but SA4503 did not affect the expression of the sigma-1 receptor. These results suggest that the protective effect of SA4503 might be involved in promoting the phosphorylation of Akt and ERK1/2. We then investigated whether SA4503 suppressed the progression of ALS in an SOD1(G93A) ALS mouse model. SA4503 did not affect the onset time of ALS. However, it significantly extended the survival time in the SOD1(G93A) mice compared with a vehicle-treated group. These findings indicate that SA4503 is effective in suppressing motor neuron degeneration and symptom progression in ALS.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病。最近有报道称，sigma-1 受体的突变会导致青少年型 ALS。因此，sigma-1 受体的功能可能在 ALS 的病理学中很重要。在本研究中，我们研究了 sigma-1 受体激动剂 SA4503 对体外和体内 ALS 模型的作用。我们首先研究了 sigma-1 受体激动剂 SA4503 是否可以预防体外 ALS 模型中 SOD1（G93A）和无血清诱导的小鼠运动神经元细胞（NSC34）的细胞死亡。在 1-10μM 的浓度下，SA4503 以浓度依赖性方式减少 SOD1（G93A）诱导的细胞死亡，sigma-1 受体拮抗剂 BD1047 抑制了 SA4503 的保护作用。接下来，我们研究了 SA4503 是否影响 Akt（Ser 473）和细胞外信号调节激酶（ERK）1/2 的磷酸化水平以及 sigma-1 受体的表达。SA4503 以时间依赖性方式促进 Akt（Ser 473）和 ERK1/2 的磷酸化，但 SA4503 不影响 sigma-1 受体的表达。这些结果表明，SA4503 的保护作用可能涉及促进 Akt 和 ERK1/2 的磷酸化。然后，我们研究了 SA4503 是否可以抑制 SOD1（G93A）ALS 小鼠模型中 ALS 的进展。SA4503 不影响 ALS 的发病时间。然而，与对照组相比，它显著延长了 SOD1（G93A）小鼠的生存时间。这些发现表明 SA4503 可有效抑制 ALS 中的运动神经元变性和症状进展。
