Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
Neurotherapeutics. 2012 Oct;9(4):814-26. doi: 10.1007/s13311-012-0140-y.
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy, and paralysis due to the loss of upper and lower motoneurons (MNs). Sigma-1 receptor (sigma-1R) activation promotes neuroprotection after ischemic and traumatic injuries to the central nervous system. We recently reported that sigma-1R agonist (PRE-084) improves the survival of MNs after root avulsion injury in rats. Moreover, a mutation of the sigma-1R leading to frontotemporal lobar degeneration/amyotrophic lateral sclerosis (ALS) was recently described in human patients. In the present study, we analyzed the potential therapeutic effect of the sigma-1R agonist (PRE-084) in the SOD1(G93A) mouse model of ALS. Mice were daily administered with PRE-084 (0.25 mg/kg) from 8 to 16 weeks of age. Functional outcome was assessed by electrophysiological tests and computerized analysis of locomotion. Histological, immunohistochemical analyses and Western blot of the spinal cord were performed. PRE-084 administration from 8 weeks of age improved the function of MNs, which was manifested by maintenance of the amplitude of muscle action potentials and locomotor behavior, and preserved neuromuscular connections and MNs in the spinal cord. Moreover, it extended survival in both female and male mice by more than 15 %. Delayed administration of PRE-084 from 12 weeks of age also significantly improved functional outcome and preservation of the MNs. There was an induction of protein kinase C-specific phosphorylation of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in SOD1(G93A) animals, and a reduction of the microglial reactivity compared with untreated mice. PRE-084 exerts a dual therapeutic contribution, modulating NMDA Ca(2+) influx to protect MNs, and the microglial reactivity to ameliorate the MN environment. In conclusion, sigma-1R agonists, such as PRE-084, may be promising candidates for a therapeutical strategy of ALS.
肌萎缩侧索硬化症是一种神经退行性疾病，其特征是由于上下运动神经元（MNs）的丧失而导致进行性无力、肌肉萎缩和瘫痪。西格玛-1 受体（sigma-1R）的激活可促进中枢神经系统缺血性和创伤性损伤后的神经保护。我们最近报道，sigma-1R 激动剂（PRE-084）可改善大鼠神经根撕脱伤后 MNs 的存活。此外，最近在人类患者中描述了导致额颞叶变性/肌萎缩侧索硬化症（ALS）的 sigma-1R 突变。在本研究中，我们分析了 sigma-1R 激动剂（PRE-084）在 SOD1（G93A）肌萎缩侧索硬化症小鼠模型中的潜在治疗效果。从 8 周龄开始，每天给小鼠给予 PRE-084（0.25mg/kg）。通过电生理学测试和运动行为的计算机分析评估功能结果。对脊髓进行组织学、免疫组织化学分析和 Western blot。从 8 周龄开始给予 PRE-084 可改善 MNs 的功能，表现为肌肉动作电位幅度和运动行为的维持，并保持脊髓中的神经肌肉连接和 MNs。此外，它使雌雄小鼠的存活率延长了 15%以上。从 12 周龄开始延迟给予 PRE-084 也显著改善了功能结果和 MNs 的保存。SOD1（G93A）动物中 NMDA 受体 NR1 亚基的蛋白激酶 C 特异性磷酸化被诱导，与未处理的小鼠相比，小胶质细胞的反应性降低。PRE-084 发挥双重治疗作用，调节 NMDA Ca（2+）内流以保护 MNs，并调节小胶质细胞反应以改善 MN 环境。总之，sigma-1R 激动剂，如 PRE-084，可能是肌萎缩侧索硬化症治疗策略的有前途的候选药物。
