Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson's disease models through activating the MEF2-PGC1α and BDNF/CREB pathways
Neuroprotective and neurogenic effects of novel tetramethylpyrazine derivative T-006 in Parkinson's disease models through activating the MEF2-PGC1α and BDNF/CREB pathways
复制标题
新型四甲基吡嗪衍生物 T-006 通过激活 MEF2-PGC1 α 和 BDNF/CREB 通路在帕金森病模型中的神经保护和神经源性作用
DOI：
10.18632/aging.103551
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发表时间：
2020-07-31
期刊：
影响因子：
5.2
通讯作者：
Wang, Yuqiang
中科院分区：
文献类型：
--
作者：
Chen, Haiyun;Cao, Jie;Wang, Yuqiang
T-006是一种新型的四甲基吡嗪衍生物，最近发现它可以通过增强α-突触核蛋白（α-syn）转基因帕金森病（PD）模型中的蛋白酶体活性来保护免受6-羟基多巴胺（6-OHDA）诱导的神经元损伤并清除α-突触核蛋白（α-syn）。然而，T-006对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD模型的作用尚未被测试，并且T-006的神经保护机制尚未完全阐明。在这项研究中，我们进一步研究了T-006的神经保护和神经原性作用，并在细胞和动物PD模型中探索了其潜在的作用机制。T-006能够改善MPTP和6-OHDA诱导的动物的运动行为，增加黑质多巴胺能神经元的存活，并提高纹状体多巴胺水平。T-006治疗通过调节Akt/GSK 3 β信号传导恢复了肌细胞增强因子2D（MEF 2D）、过氧化物酶体增殖物激活受体γ（PPAR γ）共激活因子1 α（PGC 1 β）和NF-E2相关因子1/2（Nrf 1/2）的表达改变。T-006刺激MEF 2、PGC 1 α和Nrf 2转录活性，诱导Nrf 2核定位。有趣的是，在6-OHDA大鼠中，T-006通过激活脑源性神经营养因子（BDNF）和cAMP反应元件结合蛋白（CREB）促进内源性成体神经发生向多巴胺能表型发展。我们的工作表明，T-006是一种有效的神经保护和神经再生剂，可能在PD治疗中具有治疗潜力。
T-006, a new derivative of tetramethylpyrazine, has been recently found to protect against 6-hydroxydopamine (6-OHDA)-induced neuronal damage and clear alpha-synuclein (alpha-syn) by enhancing proteasome activity in an alpha-syn transgenic Parkinson's disease (PD) model. The effect of T-006 on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD model, however, has not been tested and T-006's neuroprotective mechanisms have not been fully elucidated. In this study, we further investigated the neuroprotective and neurogenic effects of T-006 and explored its underlying mechanism of action in both cellular and animal PD models. T-006 was able to improve locomotor behavior, increase survival of nigra dopaminergic neurons and boost striatal dopamine levels in both MPTP- and 6-OHDA-induced animals. T-006 treatment restored the altered expressions of myocyte enhancer factor 2D (MEF2D), peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1 alpha (PGC1 beta) and NF-E2-related factor 1/2 (Nrf1/2) via modulation of Akt/GSK3 beta signaling. T-006 stimulated MEF2, PGC1 alpha and Nrf2 transcriptional activities, inducing Nrf2 nuclear localization. Interestingly, T-006 promoted endogenous adult neurogenesis toward a dopaminergic phenotype by activating brain-derived neurotrophic factor (BDNF) and cAMP responsive element-binding protein (CREB) in 6-OHDA rats. Our work demonstrated that T-006 is a potent neuroprotective and neuroregenerative agent that may have therapeutic potential in the treatment of PD.