Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Exp Neurol. 2019 Dec;322:113065. doi: 10.1016/j.expneurol.2019.113065. Epub 2019 Sep 16.
Progressive multiple sclerosis (PMS) is a devastating disorder sustained by neuroimmune interactions still wait to be identified. Recently, immune-independent, neural bioenergetic derangements have been hypothesized as causative of neurodegeneration in PMS patients. To gather information on the immune and neurodegenerative components during PMS, in the present study we investigated the molecular and cellular events occurring in a Non-obese diabetic (NOD) mouse model of experimental autoimmune encephalomyelitis (EAE). In these mice, we also evaluated the effects of clinically-relevant immunosuppressive (dexamethasone) or bioenergetic drugs (bezafibrate and biotin) on functional, immune and neuropathological parameters. We found that immunized NOD mice progressively accumulated disability and severe neurodegeneration in the spinal cord. Unexpectedly, although CD4 and CD8 lymphocytes but not B or NK cells infiltrate the spinal cord linearly with time, their suppression by different dexamethasone treatment schedules did not affect disease progression. Also, the spreading of the autoimmune response towards additional immunogenic myelin antigen occurred neither in the periphery nor in the CNS of EAE mice. Conversely, we found that altered mitochondrial morphology, reduced contents of mtDNA and decreased transcript levels for respiratory complex subunits occurred at early disease stages and preceded axonal degeneration within spinal cord columns. However, the mitochondria boosting drugs, bezafibrate and biotin, were unable to reduce disability progression. Data suggest that EAE NOD mice recapitulate some features of PMS. Also, by showing that bezafibrate or biotin do not affect progression in NOD mice, our study suggests that this model can be harnessed to anticipate experimental information of relevance to innovative treatments of PMS.
进行性多发性硬化症（PMS）是一种由神经免疫相互作用维持的破坏性疾病，其仍有待确定。最近，免疫独立的神经生物能量紊乱被假设为 PMS 患者神经退行性变的原因。为了在 PMS 期间收集有关免疫和神经退行性变成分的信息，在本研究中，我们研究了实验性自身免疫性脑脊髓炎（EAE）的非肥胖型糖尿病（NOD）小鼠模型中发生的分子和细胞事件。在这些小鼠中，我们还评估了临床上相关的免疫抑制（地塞米松）或生物能量药物（苯扎贝特和生物素）对功能、免疫和神经病理学参数的影响。我们发现，免疫的 NOD 小鼠逐渐出现残疾和严重的脊髓神经退行性变。出乎意料的是，尽管 CD4 和 CD8 淋巴细胞，但不是 B 或 NK 细胞，随着时间的推移线性浸润脊髓，但它们通过不同的地塞米松治疗方案抑制并没有影响疾病进展。此外，自身免疫反应向额外的免疫原性髓鞘抗原的扩散既没有发生在 EAE 小鼠的外周也没有发生在中枢神经系统中。相反，我们发现，线粒体形态改变、mtDNA 含量减少和呼吸复合物亚基的转录水平降低发生在疾病早期阶段，并先于脊髓柱内轴突变性。然而，线粒体增强药物苯扎贝特和生物素无法减少残疾进展。数据表明，EAE NOD 小鼠再现了 PMS 的一些特征。此外，通过表明苯扎贝特或生物素不会影响 NOD 小鼠的进展，我们的研究表明，该模型可用于预测与 PMS 创新治疗相关的实验信息。
