Kaneko Shinjiro, Wang Jing, Kaneko Marie, Yiu Glenn, Hurrell Joanna M, Chitnis Tanuja, Khoury Samia J, He Zhigang
Division of Neuroscience, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2006 Sep 20;26(38):9794-804. doi: 10.1523/JNEUROSCI.2116-06.2006.
Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named "Wallerian degeneration slow" (Wld(S)), can protect axons from degeneration, likely through a beta-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wld(S) mice showed a modest attenuation of behavioral deficits and axon loss, suggesting that EAE-associated axon damage may occur by a mechanism similar to Wallerian degeneration. Furthermore, nicotinamide (NAm), an NAD biosynthesis precursor, profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits in EAE models. Finally, we demonstrate that delayed NAm treatment is also beneficial to EAE models, pointing to the therapeutic potential of NAm as a protective agent for EAE and perhaps MS patients.
轴突损伤是多发性硬化症（MS）患者及其动物模型实验性自身免疫性脑脊髓炎（EAE）中枢神经系统中的一种主要形态学改变。然而，与MS/EAE相关的轴突损伤的潜在机制及其对临床症状的影响仍不清楚。一种名为“沃勒变性慢”（Wld(S)）的融合蛋白的表达可以保护轴突免于退化，可能是通过一种依赖于β-烟酰胺腺嘌呤二核苷酸（NAD）的机制。在本研究中，我们发现，在用EAE诱导时，Wld(S)小鼠的行为缺陷和轴突损失有适度减轻，这表明与EAE相关的轴突损伤可能通过类似于沃勒变性的机制发生。此外，烟酰胺（NAm），一种NAD生物合成前体，能显著防止脱髓鞘轴突的退化，并改善EAE模型中的行为缺陷。最后，我们证明延迟给予NAm治疗对EAE模型也有益，这表明NAm作为EAE以及可能对MS患者的保护剂具有治疗潜力。
