Molecular Neurobiology Unit, IBMC- Instituto de Biologia Molecular e Celular, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.
Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages. In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease.
家族性淀粉样多发性神经病（FAP）是一种以细胞外纤维状转甲状腺素（TTR）淀粉沉积为特征的疾病，特别涉及外周神经。我们之前的研究表明，在饮用水中以 40mg/Kg/ml 的剂量连续给药 3 个月的强力霉素，能够清除老年 TTR-V30M 转基因小鼠胃中的 TTR 淀粉样沉积物；这种清除伴随着伴随纤维状沉积的细胞外基质重塑蛋白的减少，但不减少非纤维状 TTR 的沉积和/或与预纤维状沉积相关的标志物。另一方面，牛磺熊脱氧胆酸（TUDCA）是一种胆酸，在相同的小鼠模型中被证明可以有效地降低沉积的非纤维状 TTR，以及与预纤维状 TTR 相关的标志物的水平，但仅在年轻时有效。在本工作中，我们评估了不同的强力霉素给药方案，包括不同的治疗期、不同的剂量和不同的 FAP TTR V30M 动物模型。评估包括 CR 染色、TTR 的免疫组织化学、金属蛋白酶 9（MMP-9）和血清淀粉样蛋白 P 成分（SAP）。我们确定，15 天的最小治疗期，每天 8mg/Kg 的剂量，可导致纤维清除。还评估了间歇性治疗的可能性，并确定了 15 天的最大暂停期，以保持组织无淀粉样物质。用两种不同浓度的强力霉素和 TUDCA 联合治疗有淀粉样沉积物的小鼠，比单独使用强力霉素或 TUDCA 更有效，可显著降低 TTR 沉积和相关组织标志物。在转基因 TTR 小鼠模型中，观察到强力霉素/TUDCA 的协同作用在人类可耐受的剂量范围内，提示它们在 FAP 中的应用，特别是在疾病的早期阶段。
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