The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease
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DOI：
10.1016/j.nbd.2014.08.021
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发表时间：
2015-01-01
影响因子：
6.1
通讯作者：
Ribeiro, F. M.
中科院分区：
文献类型：
--
作者：
Doria, J. G.;de Souza, J. M.;Ribeiro, F. M.
亨廷顿病 (HD) 是一种常染色体显性神经退行性疾病，由亨廷顿蛋白 (htt) 氨基末端区域的聚谷氨酰胺扩增引起，导致运动功能障碍、认知能力下降、精神改变和死亡。代谢型谷氨酸受体 5 (mGluR5) 与 HD 相关，我们最近证明 mGluR5 正变构调节剂 (PAM) 在体外具有神经保护作用。在本研究中，我们证明 mGluR5 PAM（CDPPB）是一种在体外和体内有效的神经保护药物，能够延缓 HD 相关症状。 HD 小鼠模型 BACHD 表现出许多 HD 特征，包括神经元细胞丢失、htt 聚集、运动不协调和记忆障碍。然而，用 CDPPB 1.5 mg/kg 皮下注射长期治疗 BACHD 小鼠。持续 18 周，增加了对神经元存活至关重要的细胞信号通路的激活，包括增加 AKT 和 ERK1/2 磷酸化以及增强 BDNF mRNA 表达。 CDPPB 慢性治疗还能够防止 BACHD 小鼠纹状体中发生的神经元细胞损失，并减少命中聚集体的形成。此外，CDPPB 慢性治疗可有效部分改善 BACHD 小鼠的运动不协调并挽救其表现出的记忆缺陷。重要的是，在 CDPPB 长期治疗中没有观察到毒性作用或刻板行为。因此，CDPPB 是治疗 HD 的潜在药物，可防止神经元细胞损失和聚集形成并延缓 HD 症状。 (C) 2015 爱思唯尔公司保留所有权利。
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein (htt), leading to motor dysfunction, cognitive decline, psychiatric alterations, and death. The metabotropic glutamate receptor 5 (mGluR5) has been implicated in HD and we have recently demonstrated that mGluR5 positive allosteric modulators (PAMs) are neuroprotective in vitro. In the present study we demonstrate that the mGluR5 PAM, CDPPB, is a potent neuroprotective drug, in vitro and in vivo, capable of delaying HD-related symptoms. The HD mouse model, BACHD, exhibits many HD features, including neuronal cell loss, htt aggregates, motor incoordination and memory impairment. However, chronic treatment of BACHD mice with CDPPB 1.5 mg/kg s.c. for 18 weeks increased the activation of cell signaling pathways important for neuronal survival, including increased AKT and ERK1/2 phosphorylation and augmented the BDNF mRNA expression. CDPPB chronic treatment was also able to prevent the neuronal cell loss that takes place in the striatum of BACHD mice and decrease hit aggregate formation. Moreover, CDPPB chronic treatment was efficient to partially ameliorate motor incoordination and to rescue the memory deficit exhibited by BACHD mice. Importantly, no toxic effects or stereotypical behavior were observed upon CDPPB chronic treatment Thus, CDPPB is a potential drug to treat HD, preventing neuronal cell loss and hit aggregate formation and delaying HD symptoms. (C) 2015 Elsevier Inc All rights reserved.