7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington's disease mouse model through specific activation of the PLCγ1 pathway
7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington's disease mouse model through specific activation of the PLCγ1 pathway
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DOI：
10.1093/hmg/ddx198
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发表时间：
2017-08-15
影响因子：
3.5
通讯作者：
Alberch, Jordi
中科院分区：
文献类型：
--
作者：
Garcia-Diaz Barriga, Gerardo;Giralt, Albert;Alberch, Jordi
亨廷顿氏病（HD）是一种致命的神经退行性疾病，伴有运动、认知和精神障碍。HD模型的功能障碍与纹状体脑源性神经营养因子（BDNF）水平降低及其受体TrkB和p75（NTR）之间的失衡有关。因此，对BDNF/TrkB/p75系统具有活性的分子可能具有治疗潜力。7,8-二羟黄酮（7,8- dhf）在几种神经退行性疾病模型中被描述为TrkB激动剂，然而，由于其多效性和与BDNF作用的差异，其TrkB激活谱需要进一步研究。为了研究这一点，我们使用体外和体内HD模型来解剖7,8- dhf处理后TrkB的激活。在原代培养中，7,8- dhf处理显示TrkB（Y816）磷酸化，而TrkB（Y515）未磷酸化，激活PLC γ 1通路，导致形态和功能改善。长期给药7,8- dhf可延迟R6/1小鼠的运动缺陷，并在17周时逆转新物体识别测试（NORT）的缺陷。形态学和生化分析显示纹状体脑啡肽水平提高，防止纹状体体积损失。我们发现在纹状体中TrkB（Y816）磷酸化恢复，而不是TrkB（Y515）磷酸化恢复，与体外结果一致。此外，7,8- dhf使纹状体诱导型和神经元型一氧化氮合酶（iNOS和nNOS）水平正常化，并改善p75/TrkB失衡。我们的研究结果为7,8- dhf的作用机制提供了新的见解，表明其通过纹状体TrkB受体的作用是通过其Y816残基的选择性磷酸化和PLC γ 1通路的激活，但该药物的多效性也有助于其治疗潜力。
Huntington's disease (HD) is a fatal neurodegenerative disease with motor, cognitive and psychiatric impairment. Dysfunctions in HD models have been related to reduced levels of striatal brain-derived neurotrophic factor (BDNF) and imbalance between its receptors TrkB and p75(NTR). Thus, molecules with activity on the BDNF/TrkB/p75 system can have therapeutic potential. 7,8-Dihydroxyflavone (7,8-DHF) was described as a TrkB agonist in several models of neuro-degenerative diseases, however, its TrkB activation profile needs further investigation due to its pleiotropic properties and divergence from BDNF effect. To investigate this, we used in vitro and in vivo models of HD to dissect TrkB activation upon 7,8-DHF treatment. 7,8-DHF treatment in primary cultures showed phosphorylation of TrkB(Y816) but not TrkB(Y515) with activation of the PLC gamma 1 pathway leading to morphological and functional improvements. Chronic administration of 7,8-DHF delayed motor deficits in R6/1 mice and reversed deficits on the Novel Object Recognition Test (NORT) at 17 weeks. Morphological and biochemical analyses revealed improved striatal levels of enkephalin, and prevention of striatal volume loss. We found a TrkB(Y816) but not TrkB(Y515) phosphorylation recovery in striatum concordant with in vitro results. Additionally, 7,8-DHF normalized striatal levels of induced and neuronal nitric oxide synthase (iNOS and nNOS, respectively) and ameliorated the imbalance of p75/TrkB. Our results provide new insights into the mechanism of action of 7,8-DHF suggesting that its effect through the TrkB receptor in striatum is via selective phosphorylation of its Y816 residue and activation of PLC gamma 1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential.