Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1.
Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1.
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DOI：
10.1186/1756-6606-6-48
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发表时间：
2013-11-19
期刊：
影响因子：
3.6
通讯作者：
Nicoletti F
中科院分区：
文献类型：
--
作者：
Notartomaso S;Zappulla C;Biagioni F;Cannella M;Bucci D;Mascio G;Scarselli P;Fazio F;Weisz F;Lionetto L;Simmaco M;Gradini R;Battaglia G;Signore M;Puliti A;Nicoletti F
脊髓小脑性共济失调1型（SCA1）是一种以小脑浦肯野细胞进行性丧失相关的严重共济失调为特征的遗传性疾病。mGlu1代谢性谷氨酸受体在小脑活动依赖的突触可塑性机制中起关键作用，其功能障碍与SCA1相关的运动症状的病理生理有关。我们使用SCA1杂合转基因小鼠（Q154/Q2）作为模型来验证增强mGlu1受体功能的药物可能是治疗SCA1的良好候选者。症状性30周龄SCA1小鼠小脑mGlu1受体mRNA和蛋白水平降低。有趣的是，这些小鼠在小脑浦肯野细胞中也表现出mGlu5受体的强烈表达，而这些细胞通常缺乏这些受体。用mGlu1受体阳性变构调节剂（PAM） Ro0711401 （10 mg/kg, s.c）对SCA1小鼠进行全身治疗，在旋转棒和爪印测试中导致运动性能的长期改善。单次注射Ro0711401可改善数天的运动症状，并且对该药物没有产生耐受性。相比之下，mGlu5受体PAM VU0360172 （10 mg/kg, s.c）仅引起运动症状的短期改善，而mGlu1受体拮抗剂JNJ16259685 （2.5 mg/kg, i.p）进一步损害了SCA1小鼠的运动表现。Ro0711401引起的长期症状获益持续时间超过了小脑药物清除的时间，并且与小脑的神经适应性变化有关，例如浦肯野细胞中异位表达的mGlu5受体显著减少，AMPA受体总磷酸化和ser880磷酸化的GluA2亚基水平增加，浦肯野细胞远端树突棘长度变化。这些数据表明，mGlu1受体的药理学增强导致SCA1小鼠运动功能的强健和持续改善，并为开发mGlu1受体pam作为治疗人类SCA1的新型“小脑特异性”、有效和安全的对症药物奠定了基础。
Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel “cerebellum-specific”, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.
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影响因子：
25
作者：
Lin, X;Antalffy, B;Zoghbi, HY
通讯作者：
Zoghbi, HY
影响因子：
5.3
作者：
Hourez, Raphael;Servais, Laurent;Schiffmann, Serge N.
通讯作者：
Schiffmann, Serge N.
影响因子：
3
作者：
GLASER, EM;VANDERLOOS, H
通讯作者：
VANDERLOOS, H
影响因子：
64.8
作者：
CONQUET, F;BASHIR, ZI;CREPEL, F
通讯作者：
CREPEL, F
影响因子：
16.2
作者：
Kano, M;Hashimoto, K;Tonegawa, S
通讯作者：
Tonegawa, S