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I. International Advances in Molecular Biology, İstanbul, Turkey, 19 - 22 September 2022, pp.55-56
Multiple sclerosis (MS) is a common disease affecting about 2.9 million people worldwide. It is a chronic demyelinating autoimmune disease with a complex genetic background of unknown primary etiology. MS treatment has received much attention, yet there is still no certain cure. We herein investigate the potential therapeutic effect of a natural compound olean-12-en-28-ol, 3β pentacosanoate (OPCA) on the preclinical model of MS, i.e., EAE. First, OPCA was synthesized semi-synthetically and characterized. OPCA was also coupled with biotin to monitor the OPC in the cell and identify the proteins with which it interacts. Then, the mice with MOG35–55-induced EAE were given OPCA or vehicle, along with a reference drug (FTY720), and their clinical symptoms were monitored on a daily basis. Biochemical, cellular, and molecular analyses were performed in serum and brain tissues to measure anti-inflammatory and neuroprotective responses. To detect and localize the molecular targets of the OPC within the cell, biotin-streptavidin pulldown and LC-MS/MS proteomics analysis and immunostaining studies were applied, respectively. The purity and the structure of the OPCA were confirmed with NMR and MS analyses. OPCA treatment protected EAE-induced changes in mice's brains, maintaining blood-brain barrier integrity and preventing inflammation. Bain levels of inflammatory infiltrating cells were consistently and significantly reduced in OPCA-treated EAE mice. Moreover, the protein and mRNA levels of MS-associated genes such as HLD-DR1, CCL5, TNFA, IL6, and TGFB1 were significantly reduced in OPCA-treated mice. Notably, expression of genes including PLP, MBP, and MAG involved in the development and structure of myelin was significantly elevated in OPCA-treated EAE but was not observed with the reference drug. Furthermore, therapeutic OPCA effects included a substantial reduction in pro-inflammatory cytokines in the serum of treated EAE animals. Lastly, following OPCA treatment, the CpG island of the promoter regions for the majority of inflammatory regulators was hypermethylated. It was found that biotinylated OPC is localized in the cell, especially in the ER in close vicinity to the nucleus and the ribosomes, on which were located. Several proteins were identified with proteomics to be the target of the OPCA, but studies are still underway to confirm. These data show that OPCA ameliorates brain abnormalities in EAE mice. It supports the hypothesis that OPCA is a valuable multitargeting molecule for treating the disease and is an appealing candidate for human MS treatment since OPCA not only normalizes the pro- and anti-inflammatory immunological bias but also stimulates remyelination in EAE via targeting proteins expressed in ER.
Keywords: Experimental Autoimmune Encephalomyelitis (EAE), Remyelination, Anti-Inflammatory, Multiple Sclerosis, Olean-12-En-28-Ol, 3β Pentacosanoate (OPCA), Cytokines, Proteomics