Penberthy W Todd, Tsunoda Ikuo
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45237, USA.
Curr Pharm Des. 2009;15(1):64-99. doi: 10.2174/138161209787185751.
The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld(S) mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld(S) genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NAD-complementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.
多发性硬化症（MS）的病因尚不清楚，但它表现为中枢神经系统（CNS）的一种慢性炎症性脱髓鞘疾病。在慢性中枢神经系统炎症期间，烟酰胺腺嘌呤二核苷酸（NAD）浓度会通过（辅助性T细胞）Th1衍生的细胞因子，在致病性小胶质细胞和淋巴细胞中协同诱导吲哚胺2,3-双加氧酶（IDO）和ADP环化酶CD38而发生改变。虽然IDO的激活可能会抑制自身反应性T细胞，但IDO的过度激活会使中枢神经系统神经元细胞缺乏细胞外NAD来源。现有数据表明，在应激期间，神经胶质细胞作为NAD的重要供应者可能发挥关键作用。给予药理剂量的非色氨酸NAD前体可改善MS动物模型中的发病机制。MS动物模型包括通过实验性自身免疫性脑脊髓炎（EAE）人工刺激对髓鞘的自身免疫攻击，或使用泰勒氏鼠脑脊髓炎病毒（TMEV）进行病毒介导的脱髓鞘。Wld（S）小鼠对剃刀切断介导的轴突变性具有显著抗性。这种抗性是由于NAD生物合成效率提高，延迟了应激诱导的轴突NAD和ATP耗竭。尽管Wld（S）基因型可预防EAE发病机制，但TMEV介导的发病机制会加剧。在本综述中，我们对比了NAD在EAE与TMEV脱髓鞘发病机制中的作用，以增进我们对NAD信号转导途径药物治疗潜力的理解。我们推测了SIRT1活性增加在PARP-1抑制中的重要性，以及神经元CD200通过神经胶质细胞CD200R相互作用在MS发病机制中诱导IDO的潜在重要作用。本文对MS发病机制中NAD生物合成和降解的免疫调节控制进行了全面综述。概述了为NAD补充或靶向以NAD为中心蛋白（SIRT1、SIRT2、PARP-1、GPR109a和CD38）设计的独特药理方法，以确定哪种方法在临床应用中可能效果最佳。
