In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin.
In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin.
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DOI：
10.1016/j.nbd.2016.02.018
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发表时间：
2016-07
影响因子：
6.1
通讯作者：
Teismann P
中科院分区：
文献类型：
--
作者：
Santoro M;Maetzler W;Stathakos P;Martin HL;Hobert MA;Rattay TW;Gasser T;Forrester JV;Berg D;Tracey KJ;Riedel G;Teismann P
高迁移率族蛋白1(HMGB1)是一种核蛋白和胞浆蛋白，在组织损伤过程中从免疫和非免疫细胞-包括小胶质细胞和神经元-释放出来。HMGB1可促进多种慢性炎症性和自身免疫性疾病的进展，这部分是通过与晚期糖基化终产物受体(RAGE)的相互作用而介导的。越来越多的体外研究表明，HMGB1可能与帕金森病(PD)的两个主要病理生理成分有关，即进行性多巴胺能变性和慢性神经炎，这是帕金森病进展的机制基础。对帕金森病患者的组织和生物液样本的分析显示，人死后黑质标本以及帕金森病患者的脑脊液和血清中HMGB1水平升高。在亚急性给予1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)诱导的帕金森病小鼠模型中，全身应用抗HMGB1中和抗体可部分抑制多巴胺能细胞死亡，减少RAGE和肿瘤坏死因子-α的升高。天然小分子甘草酸可直接与HMGB1结合，抑制MPTP诱导的HMGB1和RAGE上调，并呈剂量依赖关系减少MPTP诱导的多巴胺能细胞死亡。这些结果首次提供了体内证据，表明HMGB1在帕金森病模型中在进行性多巴胺能神经变性和慢性神经炎症之间起着强大的桥梁作用，表明HMGB1是帕金森病神经保护试验的合适靶点。HMGB1在帕金森氏病中上调。MPTP后，HMGB1转位到细胞质中。抑制HMGB1对MPTP的毒性有保护作用。抑制中和抗体或甘草酸后，HMGB1的转位减少。
High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells — including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD. HMGB1 is up-regulated in Parkinson's disease. HMGB1 is translocalized into the cytoplasm after MPTP. Inhibition of HMGB1 protects against MPTP-toxicity. Translocalization of HMGB1 is reduced after inhibition a neutralizing antibody or glycyrrhizin.