Nadeem Ahmed, Ahmad Sheikh F, Al-Harbi Naif O, Sarawi Wedad, Attia Sabry M, Alanazi Wael A, Ibrahim Khalid E, Alsanea Sary, Alqarni Saleh A, Alfardan Ali S, Bakheet Saleh A
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2022 Jun;107:108703. doi: 10.1016/j.intimp.2022.108703. Epub 2022 Mar 17.
Multiple sclerosis (MS) is characterized by chronic autoimmune inflammation of central nervous system (CNS), i.e. brain and spinal cord. Autoimmune inflammation of the CNS and periphery causes demyelination of axons ultimately leading to clinical symptoms such as gait imbalance, lack of coordination and paraplegia. Innate immune cells such as dendritic cells and neutrophils play a critical role in the initiation and progression of MS through upregulation of oxidants. Two prominent pathways that play important role in regulation of oxidant-antioxidant balance are nuclear factor-erythroid factor 2-related factor 2(Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Nrf2-mediated upregulation of antioxidants counteracts NF-κB-mediated oxidant generation. Therefore, this study evaluated the effects of nutraceutical drug, acetyl-11-keto-β-boswellic acid (AKBA) in relapsing remitting model of experimental autoimmune encephelomyelitis (EAE). Efficacy of AKBA was explored on clinical symptoms, Nrf2, hemeoxygenase-1 (HO-1), NF-κB, inducible nitric oxide synthase (iNOS) in CNS and periphery of SJL/J mice. Our results show that expression of p-NF-κB and iNOS is elevated, whereas expression of Nrf2 and HO-1 is decreased in CD11c + DCs and CNS, which is linked with appearance of clinical symptoms in immunized SJL/J mice. Treatment of immunized SJL/J mice with AKBA causes improvement of clinical symptoms and downregulation of inflammatory markers in CD11c + DCs (p-NF-κB, iNOS, and nitrotyrosine), and CNS (p-NF-κB, iNOS, nitrotyrosine,lipid peroxides, and total antioxidant capacity). Treatment of immunized SJL/J mice with AKBA also causes rectification of Nrf2 signaling in CD11c + DCs, and CNS. These results propose AKBA ameliorates EAE disease progression through rectification of Nrf2 signaling and attenuation of NF-κB pathway in RR model of EAE. Therefore, nutraceutical compound, AKBA may be therapeutically useful in RRMS.
多发性硬化症（MS）的特征是中枢神经系统（CNS），即脑和脊髓的慢性自身免疫性炎症。中枢神经系统和外周的自身免疫性炎症会导致轴突脱髓鞘，最终引发步态失衡、协调能力缺失和截瘫等临床症状。树突状细胞和中性粒细胞等固有免疫细胞通过上调氧化剂在MS的发生和发展中起关键作用。在调节氧化剂 - 抗氧化剂平衡中起重要作用的两条突出途径是核因子 - 红细胞系衍生2相关因子2（Nrf2）和活化B细胞的核因子κ轻链增强子（NF-κB）。Nrf2介导的抗氧化剂上调可抵消NF-κB介导的氧化剂生成。因此，本研究评估了营养药物乙酰 - 11 - 酮 - β - 乳香酸（AKBA）在实验性自身免疫性脑脊髓炎（EAE）复发缓解模型中的作用。探讨了AKBA对SJL/J小鼠中枢神经系统和外周的临床症状、Nrf2、血红素加氧酶 - 1（HO-1）、NF-κB、诱导型一氧化氮合酶（iNOS）的疗效。我们的结果表明，在CD11c + DC和中枢神经系统中，p-NF-κB和iNOS的表达升高，而Nrf2和HO-1的表达降低，这与免疫的SJL/J小鼠临床症状的出现有关。用AKBA治疗免疫的SJL/J小鼠可改善临床症状，并下调CD11c + DC（p-NF-κB、iNOS和硝基酪氨酸）和中枢神经系统（p-NF-κB、iNOS、硝基酪氨酸、脂质过氧化物和总抗氧化能力）中的炎症标志物。用AKBA治疗免疫的SJL/J小鼠还可纠正CD11c + DC和中枢神经系统中的Nrf2信号传导。这些结果表明，AKBA通过纠正Nrf2信号传导和减弱EAE复发缓解模型中的NF-κB途径来改善EAE疾病进展。因此，营养化合物AKBA可能对复发缓解型多发性硬化症（RRMS）具有治疗作用。
