Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease.
Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease.
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DOI：
10.1111/bph.12164
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发表时间：
2013-06
影响因子：
7.3
通讯作者：
Ribeiro FM
中科院分区：
文献类型：
--
作者：
Doria JG;Silva FR;de Souza JM;Vieira LB;Carvalho TG;Reis HJ;Pereira GS;Dobransky T;Ribeiro FM
亨廷顿氏病（HD）是一种常染色体显性神经退行性疾病，由亨廷顿蛋白中聚谷氨酰胺扩增引起。我们之前已经证明，代谢性谷氨酸受体5 （mGluR5）的细胞信号传导在HD小鼠模型中发生了改变。虽然mglur5依赖的保护通路在HD神经元中更活跃，但细胞内Ca2+释放也更明显，这可能有助于兴奋性毒性。在本研究中，我们的目的是研究mGluR5阳性变构调节剂（PAMs）是否可以在不触发高水平Ca2+释放的情况下激活保护途径，并在HD中发挥神经保护作用。我们进行了神经元细胞死亡实验来确定哪些药物具有神经保护作用，Western blot和Ca2+释放实验来研究这种神经保护作用的分子机制，以及物体识别任务来确定测试药物是否可以改善HD记忆缺陷。我们发现mGluR5 PAMs可以保护纹状体神经元免受谷氨酸和NMDA浓度升高引起的兴奋性毒性神经元细胞死亡。mGluR5 pam能够激活Akt而不触发细胞内Ca2+浓度升高（[Ca2+]i）；Akt阻断导致pam介导的神经保护功能丧失。重要的是，mGluR5 PAMs对HD， BACHD小鼠模型纹状体神经元的神经保护作用突出了PAMs作为治疗神经退行性疾病的药物的潜力。此外，mGluR5 PAMs可以更强地激活BACHD小鼠的神经保护通路，改善HD记忆缺陷。mGluR5 PAMs是治疗神经退行性疾病，特别是HD的潜在药物。
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca2+ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca2+ release and be neuroprotective in HD. We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca2+ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit. We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca2+ concentration ([Ca2+]i); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit. mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.
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影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
影响因子：
13.8
作者：
Conn PJ;Lindsley CW;Jones CK
通讯作者：
Jones CK
mGluR5 正调节剂通过 PKC 依赖性激活 MEK/ERK 通路对创伤性神经元损伤的保护作用
影响因子：
4.4
作者：
Chen, Tao;Cao, Lei;Fei, Zhou
通讯作者：
Fei, Zhou
影响因子：
3.4
作者：
Bruno, V;Battaglia, G;Nicoletti, F
通讯作者：
Nicoletti, F
影响因子：
7.3
作者：
McGrath, J. C.;Drummond, G. B.;Wainwright, C. L.
通讯作者：
Wainwright, C. L.