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Protective Effects of Leukadherin1 in a Rat Model of Targeted Experimental Autoimmune Encephalomyelitis (EAE): Possible Role of P47phox and MDA Downregulation.
Journal of Inflammation Research ( IF 4.5 ) Pub Date : 2020-07-31 , DOI: 10.2147/jir.s258991
Sara Hemmati 1, 2, 3 , Mohammad Amin Sadeghi 1, 2, 3 , Hasan Yousefi-Manesh 2, 3 , Mostafa Eslamiyeh 4 , Ali Vafaei 2, 3 , Laleh Foroutani 2 , Ghazaleh Donyadideh 4 , AhmadReza Dehpour 3 , Nima Rezaei 5, 6, 7
Affiliation  

Background: Reactive oxygen and nitrogen species (ROS and RNS) are involved in pathologic mechanisms underlying demyelination and exacerbation in multiple sclerosis (MS) lesions. P47phox is the most important subunit of an ROS-producing enzyme (NADPH oxidase) which is reportedly upregulated in MS plaques due to the intense activity of infiltrated immune cells and resident microglia. Leukadherin1 is a specific CD11b/CD18 agonist that inhibits signaling and transmigration of inflammatory cells to sites of injury. Based on this mechanism, we evaluated therapeutic effects of leukadherin1 in an animal model of targeted experimental autoimmune encephalomyelitis (EAE) through focal injection of inflammatory cytokines to the spinal cord.
Methods: For model induction, Lewis rats were first immunized with 15μg MOG 1– 125 emulsion. Twenty days later, animals were subjected to stereotaxic injection of IFNγ and TNFα to the specific spinal area (T8). One day after injection, all animals presented EAE clinical signs, and their behaviors were monitored for eight days through open-field locomotion and grid-walking tests. Leukadherin1-treated animals received daily intraperitoneal injections of 1mg/kg of the drug. The specific spinal tissues were extracted on day 5 in order to measure nitric oxide (NO), malon di-aldehyde (MDA), and TNFα concentrations alongside P47phox real-time PCR analysis. In addition, spinal sections were prepared for immunohistochemical (IHC) observation of infiltrated leukocytes and activated microglia.
Results: Leukadherin1 exhibited promising improvements in EAE clinical scores and behavioral tests. Demyelination, CD45+ leukocyte infiltration, and Iba1+ microglia activation were reduced in spinal tissues of leukadherin1-treated animals. Furthermore, P47phox expression levels, MDA, and NO amounts were decreased in treated animals. However, TNFα concentrations did not differ following treatment.
Conclusion: Based on our results, we suggest that leukadherin1 may be used as a novel therapeutic agent in tackling the clinical challenge of multiple sclerosis, especially during the acute phase of the disease. This effect was possibly mediated through decreased leukocyte infiltration and oxidative stress.



中文翻译:

Leukadherin1 在靶向实验性自身免疫性脑脊髓炎 (EAE) 大鼠模型中的保护作用:P47phox 和 MDA 下调的可能作用。

背景:活性氧和氮(ROS 和 RNS)参与了多发性硬化症 (MS) 病变脱髓鞘和恶化的病理机制。P47phox 是产生 ROS 的酶(NADPH 氧化酶)的最重要亚基,据报道,由于浸润的免疫细胞和常驻小胶质细胞的强烈活性,它在 MS 斑块中上调。Leukadherin1 是一种特异性 CD11b/CD18 激动剂,可抑制炎症细胞向损伤部位的信号传导和迁移。基于这种机制,我们通过向脊髓局部注射炎性细胞因子来评估 leukadherin1 在靶向实验性自身免疫性脑脊髓炎 (EAE) 动物模型中的治疗效果。
方法:对于模型诱导,首先用 15μg MOG 1-125 乳液免疫 Lewis 大鼠。二十天后,动物被立体定向​​注射 IFNγ 和 TNFα 到特定的脊柱区域(T8)。注射一天后,所有动物都出现 EAE 临床症状,并通过旷场运动和网格行走测试监测它们的行为 8 天。Leukadherin1 治疗的动物每天接受 1mg/kg 药物的腹腔注射。在第 5 天提取特定的脊柱组织,以测量一氧化氮 (NO)、丙二醛 (MDA) 和 TNFα 浓度以及 P47phox 实时 PCR 分析。此外,制备脊柱切片用于浸润的白细胞和活化的小胶质细胞的免疫组织化学(IHC)观察。
结果:Leukadherin1 在 EAE 临床评分和行为测试中表现出有希望的改善。在 leukadherin1 治疗的动物的脊髓组织中,脱髓鞘、CD45+ 白细胞浸润和 Iba1+ 小胶质细胞活化减少。此外,P47phox 表达水平、MDA 和 NO 量在治疗动物中降低。然而,TNFα浓度在治疗后没有差异。
结论:根据我们的研究结果,我们建议 leukadherin1 可用作应对多发性硬化症的临床挑战的新型治疗剂,尤其是在疾病的急性期。这种作用可能是通过减少白细胞浸润和氧化应激介导的。

更新日期:2020-07-31
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