背景:多发性硬化症(MS)是中枢神经系统(CNS)的慢性自身免疫性疾病,以神经炎症为特征,脱髓鞘,和神经变性。考虑到全球年轻人的患病率增加和疾病的致残表型,需要更深入地了解疾病发病机制的复杂性,以最终改善诊断和个性化治疗机会。最近的研究结果表明,来自ω-3/-6多不饱和脂肪酸(PUFA)的生物活性脂质介质(LM),也被称为二十烷酸,可能有助于MS的发病机制。例如,在MS(PwMS)患者中,已经报道了LM谱的干扰,尤其是来自ω-6PUFA花生四烯酸(AA)的干扰,它们可能导致神经炎症过程的慢性化。此外,我们以前已经表明,某些AA衍生的LM也与PwMS中的神经退行性过程有关,表明AA衍生的LM参与更多的病理事件而不仅仅是神经炎症。然而,到目前为止,关于这些LM对MS相关病理过程的贡献的全面概述仍然难以捉摸。
方法:这篇综述总结并批判性地评估了当前关于二十烷酸生物合成途径及其在不同疾病阶段对MS关键病理标志的贡献的文献。类花生酸途径的各个部分被强调,即,前列腺素,白三烯,和羟基二十碳四烯酸(HETEs)生化途径,包括环氧合酶(COX)和脂氧合酶(LOX)家族的特定酶。此外,将在MS的背景下讨论LM的细胞来源及其基于受体表达谱的潜在靶细胞。最后,我们提出了基于类花生酸途径和/或受体调节的新型治疗方法,以最终靶向慢性神经炎症,MS的脱髓鞘和神经变性
结论:类二十烷酸途径与MS发病机制的特定方面有内在联系。因此,我们提出了新的干预策略,目的是准确地调节类花生酸途径,使其生物合成有益的LMs,可能有助于更多的患者和MS亚型特异性治疗机会来对抗MS。
BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by neuroinflammation, demyelination, and neurodegeneration. Considering the increasing prevalence among young adults worldwide and the disabling phenotype of the disease, a deeper understanding of the complexity of the disease pathogenesis is needed to ultimately improve diagnosis and personalize treatment opportunities. Recent findings suggest that bioactive lipid mediators (LM) derived from ω-3/-6 polyunsaturated fatty acids (PUFA), also termed eicosanoids, may contribute to MS pathogenesis. For example, disturbances in LM profiles and especially those derived from the ω-6 PUFA arachidonic acid (AA) have been reported in people with MS (PwMS), where they may contribute to the chronicity of neuroinflammatory processes. Moreover, we have previously shown that certain AA-derived LMs also associated with neurodegenerative processes in PwMS, suggesting that AA-derived LMs are involved in more pathological events than solely neuroinflammation. Yet, to date, a comprehensive overview of the contribution of these LMs to MS-associated pathological processes remains elusive.
METHODS: This review summarizes and critically evaluates the current body of literature on the eicosanoid biosynthetic pathway and its contribution to key pathological hallmarks of MS during different disease stages. Various parts of the eicosanoid pathway are highlighted, namely, the prostanoid, leukotriene, and hydroxyeicosatetraenoic acids (HETEs) biochemical routes that include specific enzymes of the cyclooxygenases (COXs) and lipoxygenases (LOX) families. In addition, cellular sources of LMs and their potential target cells based on receptor expression profiles will be discussed in the context of MS. Finally, we propose novel therapeutic approaches based on eicosanoid pathway and/or receptor modulation to ultimately target chronic neuroinflammation, demyelination and neurodegeneration in MS.
CONCLUSIONS: The eicosanoid pathway is intrinsically linked to specific aspects of MS pathogenesis. Therefore, we propose that novel intervention strategies, with the aim of accurately modulating the eicosanoid pathway towards the biosynthesis of beneficial LMs, can potentially contribute to more patient- and MS subtype-specific treatment opportunities to combat MS.