Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models.
Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models.
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DOI：
10.1186/1479-5876-8-74
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发表时间：
2010-07-30
影响因子：
7.4
通讯作者：
Saraiva MJ
中科院分区：
文献类型：
--
作者：
Cardoso I;Martins D;Ribeiro T;Merlini G;Saraiva MJ
家族性淀粉样多发性神经病 (FAP) 是一种以纤维状运甲状腺素蛋白 (TTR) 淀粉样蛋白细胞外沉积为特征的疾病，特别累及周围神经。我们之前已经证明，在饮用水中以 40 mg/Kg/ml 的强力霉素施用 3 个月，能够去除老年 TTR-V30M 转基因小鼠胃中存在的 TTR 淀粉样蛋白沉积物；去除伴随着纤维沉积的细胞外基质重塑蛋白的减少，但非纤维TTR沉积和/或与纤维前沉积相关的标记物没有减少。另一方面，牛磺熊去氧胆酸 (TUDCA)（一种胆汁酸）给予同一小鼠模型，可有效降低沉积的非原纤维 TTR 以及与原纤维 TTR 相关的标志物水平，但仅限于年轻小鼠。在目前的工作中，我们评估了不同的多西环素给药方案，包括不同的治疗周期、不同的剂量和不同的FAP TTR V30M动物模型。评估包括 CR 染色、TTR 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，使用 8 毫克/公斤/天的剂量进行至少 15 天的治疗可以去除原纤维。还评估了间歇治疗的可能性，并确定了最长 15 天的暂停时间，以保持组织无淀粉样蛋白。使用两种不同浓度的两种药物对具有淀粉样蛋白沉积的小鼠联合循环施用多西环素和TUDCA，在显着降低TTR沉积和相关组织标志物方面比单独使用多西环素或TUDCA更有效。在转基因 TTR 小鼠模型中观察到的多西环素/TUDCA 在人类可耐受量范围内的协同效应促进了它们在 FAP 中的应用，特别是在疾病的早期阶段。
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.
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6.1
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通讯作者：
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