Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters
Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters
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早期米诺环素和晚期 FK506 治疗可提高感染朊病毒的仓鼠的生存率并减轻神经炎症、神经变性和行为缺陷
DOI：
10.1007/s13311-016-0500-0
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发表时间：
2017-01
影响因子：
5.7
通讯作者：
Yang Lifeng
中科院分区：
文献类型：
--
作者：
Shah Syed Zahid Ali;Zhao Deming;Taglialatela Giulio;Khan Sher Hayat;Hussain Tariq;Dong Haodi;Lai Mengyu;Zhou Xiangmei;Yang Lifeng
中枢神经系统（CNS）的朊病毒感染的特征是最初的反应性神经胶质增生，随后是明显的神经元死亡。神经胶质增生最初可能是由正常细胞朊病毒蛋白 (PrPc) 的错误折叠、蛋白酶 K 抗性亚型（称为 PrPSc）在大脑中沉积引起的。 PrPSc 激活的神经胶质细胞和应激神经元释放的促炎细胞因子和趋化因子也可能通过增强神经胶质增生和诱导神经毒性直接或间接促进疾病的发展。最近的研究表明，早期神经炎症会激活钙调磷酸酶信号级联中的活化T细胞核因子（NFAT），导致核因子κB（NF-κB）核转位，促进细胞凋亡。因此，减缓朊病毒病发展进程的有效治疗方法应该控制早期炎症反应以抑制 NFAT 信号传导。在这里，我们使用朊病毒疾病的仓鼠模型首次测试了第二代半合成四环素衍生物米诺环素与具有已知 NFAT 抑制活性的钙调神经磷酸酶抑制剂 FK506 的神经保护和 NFAT 抑制作用。我们的结果表明，从朊病毒病症状前阶段开始长期使用米诺环素治疗比在朊病毒病症状前或症状阶段给予 FK506 更有效。具体来说，米诺环素治疗降低了星形胶质细胞激活标记物神经胶质纤维酸性蛋白和小胶质细胞激活标记物离子化钙结合接头分子1的表达，随后降低了促炎细胞因子白细胞介素1β和肿瘤坏死因子-α的水平。我们进一步发现米诺环素和 FK506 治疗以 caspase 依赖性方式抑制丝裂原激活蛋白激酶 p38 磷酸化和 NF-κB 核转位，并增强磷酸化环单磷酸腺苷反应元件结合蛋白和磷酸化 Bcl2 相关死亡启动子水平，从而减少认知障碍和细胞凋亡。综上所述，我们的结果表明米诺环素是长期使用朊病毒疾病的更好选择，并鼓励其进一步临床开发作为该疾病的可能治疗方法。
Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrPSc) of the normal cellular prion protein (PrPc) in the brain. Proinflammatory cytokines and chemokines released by PrPSc-activated glia and stressed neurons may also contribute directly or indirectly to the disease development by enhancing gliosis and inducing neurotoxicity. Recent studies have illustrated that early neuroinflammation activates nuclear factor of activated T cells (NFAT) in the calcineurin signaling cascade, resulting in nuclear translocation of nuclear factor kappa B (NF-κB) to promote apoptosis. Hence, useful therapeutic approaches to slow down the course of prion disease development should control early inflammatory responses to suppress NFAT signaling. Here we used a hamster model of prion diseases to test, for the first time, the neuroprotective and NFAT-suppressive effect of a second-generation semisynthetic tetracycline derivative, minocycline, versus a calcineurin inhibitor, FK506, with known NFAT suppressive activity. Our results indicate that prolonged treatment with minocycline, starting from the presymptomatic stage of prion disease was more effective than FK506 given either during the presymptomatic or symptomatic stage of prion disease. Specifically, minocycline treatment reduced the expression of the astrocyte activation marker glial fibrillary acidic protein and of the microglial activation marker ionized calcium-binding adapter molecule-1, subsequently reducing the level of proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. We further found that minocycline and FK506 treatment inhibited mitogen-activated protein kinase p38 phosphorylation and NF-κB nuclear translocation in a caspase-dependent manner, and enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein and phosphorylated Bcl2-associated death promoter levels to reduce cognitive impairment and apoptosis. Taken together, our results indicate that minocycline is a better choice for prolonged use in prion diseases and encourage its further clinical development as a possible treatment for this disease.
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米诺环素可减少神经炎症，但不能改善神经变性小鼠模型中的神经元损失。
影响因子：
4.6
作者：
Cheng S;Hou J;Zhang C;Xu C;Wang L;Zou X;Yu H;Shi Y;Yin Z;Chen G
通讯作者：
Chen G
影响因子：
15.1
作者：
Sadleir KR;Eimer WA;Cole SL;Vassar R
通讯作者：
Vassar R
影响因子：
64.8
作者：
Moreno, Julie A.;Radford, Helois;Peretti, Diego;Steinert, Joern R.;Verity, Nicholas;Martin, Maria Guerra;Halliday, Mark;Morgan, Jason;Dinsdale, David;Ortori, Catherine A.;Barrett, David A.;Tsaytler, Pavel;Bertolotti, Anne;Willis, Anne E.;Bushell, Martin;Mallucci, Giovanna R.
通讯作者：
Mallucci, Giovanna R.
影响因子：
82.9
作者：
Chen, M;Ona, VO;Friedlander, RM
通讯作者：
Friedlander, RM
DOI：
--
发表时间：
2014
期刊：
--
影响因子：
--
作者：
G. M. Arisi;M. L. Foresti;A. Montanez;Lee A. Shapiro
通讯作者：
G. M. Arisi;M. L. Foresti;A. Montanez;Lee A. Shapiro