Gutiérrez-Miranda Beatriz, Gallardo Isabel, Melliou Eleni, Cabero Isabel, Álvarez Yolanda, Magiatis Prokopios, Hernández Marita, Nieto María Luisa
Instituto de Biología y Genética Molecular (IBGM-CSIC/UVa), 47001 Valladolid, Spain.
Laboratory of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
Antioxidants (Basel). 2020 Nov 21;9(11):1161. doi: 10.3390/antiox9111161.
UNLABELLED: Oxidative stress and proinflammatory cytokines are factors affecting multiple sclerosis (MS) disease progression. Oleacein (OLE), an olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential application to treat neuroinflammatory disorders. Herein, we investigated the impact of OLE on the main clinic-pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, including paralysis, demyelination, central nervous system (CNS) inflammation/oxidative stress and blood-brain barrier (BBB) breakdown. METHODS: Mice were immunized with the myelin oligodendrocyte glycoprotein peptide, MOG to induce EAE, and OLE was administrated from immunization day. Serum, optic nerve, spinal cord and cerebellum were collected to evaluate immunomodulatory activities at a systemic level, as well as within the CNS. Additionally, BV2 microglia and the retinal ganglion cell line RGC-5 were used to confirm the direct effect of OLE on CNS-resident cells. RESULTS: We show that OLE treatment effectively reduced clinical score and histological signs typical of EAE. Histological evaluation confirmed a decrease in leukocyte infiltration, demyelination, BBB disruption and superoxide anion accumulation in CNS tissues of OLE-treated EAE mice compared to untreated ones. OLE significantly decreased expression of proinflammatory cytokines (IL-13, TNFα, GM-CSF, MCP-1 and IL-1β), while it increased the anti-inflammatory cytokine IL-10. Serum levels of anti-MOG antibodies were also lower in OLE-treated EAE mice. Further, OLE significantly diminished the presence of oxidative system parameters, while upregulated the ROS disruptor, Sestrin-3. Mechanistically, OLE prevented NLRP3 expression, phosphorylation of p65-NF-κB and reduced the synthesis of proinflammatory mediators induced by relevant inflammatory stimuli in BV2 cells. OLE did not affect viability or the phagocytic capabilities of BV2 microglia. In addition, apoptosis of RGC-5 induced by oxidative stressors was also prevented by OLE. CONCLUSION: Altogether, our results show that the antioxidant and anti-inflammatory OLE has neuroprotective effects in the CNS of EAE mice, pointing out this natural product as a candidate to consider for research on MS treatments.
未标记：氧化应激和促炎细胞因子是影响多发性硬化症（MS）疾病进展的因素。橄榄苦苷（OLE）是一种橄榄裂环烯醚萜，具有强大的抗氧化和抗炎活性，这表明其在治疗神经炎症性疾病方面具有潜在应用价值。在此，我们研究了OLE对实验性自身免疫性脑脊髓炎（EAE）主要临床病理特征的影响，EAE是MS的动物模型，包括瘫痪、脱髓鞘、中枢神经系统（CNS）炎症/氧化应激和血脑屏障（BBB）破坏。 方法：用髓鞘少突胶质细胞糖蛋白肽MOG免疫小鼠以诱导EAE，并从免疫当天开始给予OLE。收集血清、视神经、脊髓和小脑，以评估全身水平以及CNS内的免疫调节活性。此外，使用BV2小胶质细胞和视网膜神经节细胞系RGC-5来确认OLE对CNS驻留细胞的直接作用。 结果：我们表明，OLE治疗有效降低了EAE典型的临床评分和组织学体征。组织学评估证实，与未治疗的EAE小鼠相比，OLE治疗的EAE小鼠CNS组织中的白细胞浸润、脱髓鞘、BBB破坏和超氧阴离子积累减少。OLE显著降低促炎细胞因子（IL-13、TNFα、GM-CSF、MCP-1和IL-1β）的表达，同时增加抗炎细胞因子IL-10。OLE治疗的EAE小鼠血清抗MOG抗体水平也较低。此外，OLE显著减少氧化系统参数的存在，同时上调ROS破坏剂Sestrin-3。从机制上讲，OLE可防止NLRP3表达、p65-NF-κB磷酸化，并减少BV2细胞中相关炎症刺激诱导的促炎介质的合成。OLE不影响BV2小胶质细胞的活力或吞噬能力。此外，OLE还可防止氧化应激源诱导的RGC-5细胞凋亡。 结论：总之，我们的结果表明，具有抗氧化和抗炎作用的OLE在EAE小鼠的CNS中具有神经保护作用，指出这种天然产物可作为MS治疗研究的候选物。
J Neuroinflammation. 2018-6-14
Int Immunopharmacol. 2019-12-9
Biomolecules. 2024-10-8
Antioxidants (Basel). 2023-6-19
Oxid Med Cell Longev. 2020-5-12
Neurol Neuroimmunol Neuroinflamm. 2020-7
Antioxidants (Basel). 2019-12-31
Zotero 插件
