Shah Syed Zahid Ali, Zhao Deming, Taglialatela Giulio, Khan Sher Hayat, Hussain Tariq, Dong Haodi, Lai Mengyu, Zhou Xiangmei, Yang Lifeng
National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555-1044, USA.
Neurotherapeutics. 2017 Apr;14(2):463-483. doi: 10.1007/s13311-016-0500-0.
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 PrP) of the normal cellular prion protein (PrP) in the brain. Proinflammatory cytokines and chemokines released by PrP-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.
中枢神经系统（CNS）的朊病毒感染的特征是最初出现反应性胶质增生，随后是明显的神经元死亡。胶质增生最初可能是由正常细胞朊病毒蛋白（PrP）的错误折叠、蛋白酶K抗性异构体（称为PrP）在大脑中的沉积引起的。PrP激活的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胶质增生和诱导神经毒性直接或间接促进疾病发展。最近的研究表明，早期神经炎症激活钙调神经磷酸酶信号级联反应中的活化T细胞核因子（NFAT），导致核因子κB（NF-κB）的核转位，从而促进细胞凋亡。因此，减缓朊病毒疾病发展进程的有效治疗方法应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的神经保护作用和NFAT抑制作用。我们的结果表明，从朊病毒疾病的症状前期开始长期使用米诺环素比在朊病毒疾病的症状前期或症状期给予FK506更有效。具体而言，米诺环素治疗降低了星形胶质细胞活化标志物胶质纤维酸性蛋白和小胶质细胞活化标志物离子钙结合衔接分子-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治疗以半胱天冬酶依赖性方式抑制丝裂原活化蛋白激酶p38磷酸化和NF-κB核转位，并提高磷酸化环磷酸腺苷反应元件结合蛋白和磷酸化Bcl2相关死亡促进因子水平，以减少认知障碍和细胞凋亡。综上所述，我们的结果表明，米诺环素是朊病毒疾病长期使用的更好选择，并鼓励其作为该疾病的可能治疗方法进一步进行临床开发。
