Clinical and Experimental Therapeutics Program, Department of Clinical and Administrative Pharmacy, University of Georgia, Augusta, GA 30912, USA.
Research Division, Charlie Norwood VA Medical Center, Augusta, GA 30901, USA.
Int J Mol Sci. 2022 Feb 15;23(4):2133. doi: 10.3390/ijms23042133.
Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.
多胺氧化在神经退行性疾病中起主要作用。我们实验室的先前研究表明，使用 MDL 72527 抑制精脒氧化酶（SMOX，多胺氧化酶家族的成员）可减少视网膜兴奋性毒性和糖尿病性视网膜病变模型中的神经变性。但是，SMOX 抑制提供的神经保护作用的机制尚未完全研究。利用视网膜兴奋性毒性的实验模型，本研究确定了 SMOX 阻断对视网膜神经炎症的影响。我们的结果表明，在兴奋性毒性诱导的视网膜中，Iba-1（离子钙结合衔接分子 1）、CD（分化簇）68 和 CD16/32 阳性细胞的数量增加，而 MDL 72527 处理减少了这些变化，同时 Argina se1 和 CD206 阳性细胞的数量增加。当视网膜兴奋性毒性上调了几个促炎基因时，MDL 72527 处理减少了其中许多基因，并增加了抗炎基因。此外，SMOX 抑制上调了抗氧化信号（由 Nrf2 和 HO-1 水平升高表示），并减少了兴奋性视网膜中蛋白结合丙烯醛的含量。体外研究使用 C8-B4 细胞表明，细胞形态发生变化，并在对丙烯醛（SMOX 活性产物）处理的反应中形成更多的活性氧。总的来说，我们的研究结果表明，SMOX 途径的抑制减轻了视网膜中的神经炎症并上调了抗氧化信号。
