Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912, USA.
Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA.
Cells. 2022 Dec 16;11(24):4100. doi: 10.3390/cells11244100.
Multiple Sclerosis (MS) is a highly disabling neurological disease characterized by inflammation, neuronal damage, and demyelination. Vision impairment is one of the major clinical features of MS. Previous studies from our lab have shown that MDL 72527, a pharmacological inhibitor of spermine oxidase (SMOX), is protective against neurodegeneration and inflammation in the models of diabetic retinopathy and excitotoxicity. In the present study, utilizing the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined the impact of SMOX blockade on retinal neurodegeneration and optic nerve inflammation. The increased expression of SMOX observed in EAE retinas was associated with a significant loss of retinal ganglion cells, degeneration of synaptic contacts, and reduced visual acuity. MDL 72527-treated mice exhibited markedly reduced motor deficits, improved neuronal survival, the preservation of synapses, and improved visual acuity compared to the vehicle-treated group. The EAE-induced increase in macrophage/microglia was markedly reduced by SMOX inhibition. Upregulated acrolein conjugates in the EAE retina were decreased through MDL 72527 treatment. Mechanistically, the EAE-induced ERK-STAT3 signaling was blunted by SMOX inhibition. In conclusion, our studies demonstrate the potential benefits of targeting SMOX to treat MS-mediated neuroinflammation and vision loss.
多发性硬化症 (MS) 是一种高度致残的神经系统疾病，其特征为炎症、神经元损伤和脱髓鞘。视力障碍是 MS 的主要临床特征之一。我们实验室的先前研究表明，多胺氧化酶 (SMOX) 的药理学抑制剂 MDL 72527 可预防糖尿病性视网膜病变和兴奋性毒性模型中的神经退行性变和炎症。在本研究中，我们利用多发性硬化症的实验性自身免疫性脑脊髓炎 (EAE) 模型，确定了 SMOX 阻断对视网膜神经退行性变和视神经炎症的影响。EAE 视网膜中观察到的 SMOX 表达增加与视网膜神经节细胞的显著丧失、突触接触的退化以及视力下降有关。与载体处理组相比，MDL 72527 治疗的小鼠表现出明显的运动缺陷减少、神经元存活改善、突触保存和视力提高。SMOX 抑制明显减少了 EAE 诱导的巨噬细胞/小胶质细胞的增加。通过 MDL 72527 治疗，EAE 视网膜中上调的丙烯醛缀合物减少。从机制上讲，SMOX 抑制减弱了 EAE 诱导的 ERK-STAT3 信号传导。总之，我们的研究表明，针对 SMOX 治疗 MS 介导的神经炎症和视力丧失具有潜在的益处。
