Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease
Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease
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DOI：
10.1111/j.1476-5381.2012.01943.x
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发表时间：
2012-08-01
影响因子：
7.3
通讯作者：
Duty, Susan
中科院分区：
文献类型：
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作者：
Betts, Matthew J.;O'Neill, Michael J.;Duty, Susan
背景和结论我们最近报道了使用L-2-氨基-4-膦酰基丁酸酯在6-羟基多巴胺损伤的帕金森病大鼠模型中，广谱激动剂诱导的突触前III组代谢型谷氨酸（mGlu）受体的激活提供了功能性神经保护。实验方法用mGlu（4）受体的正向别构调节剂（+/-）-cis-2-（-）-cis-（3，5-二氯苯氨基甲酰基）环己烷羧酸（VU 0155041），在单侧6-羟基多巴胺损伤的大鼠中进行了研究。使用习惯性（圆筒试验）和强迫性（调整的踏步、安非他明诱导的旋转）行为试验评估VU 0155041给药对运动功能的影响。通过分析纹状体中的酪氨酸羟化酶、多巴脱羧酶或多巴胺水平以及黑质中的酪氨酸羟化酶阳性细胞计数来检查黑质纹状体束的完整性。关键词TSVU 0155041提供了约40%的组织学保护，防止单侧6-羟基多巴胺损伤，并显著保护运动功能。这些作用被（RS）-α-环丙基-4-膦酰基苯基甘氨酸预处理抑制，证实了受体介导的应答。VU 0155041治疗动物的脑中炎症标记物水平降低也是明显的。结论和意义在6-羟基多巴胺大鼠模型中，黑质丘脑旁核中mGlu（4）受体的变构增强作用提供了神经保护作用。除了所报道的症状效应之外，mGlu（4）受体的激活也可能提供一种减缓帕金森病中观察到的进行性变性的新方法。
BACKGROUND AND PURPOSEWe recently reported that broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the substantia nigra pars compacta using L-2-amino-4-phosphonobutyrate provided functional neuroprotection in the 6-hydroxydopamine lesion rat model of Parkinson's disease. The aim of this study was to establish whether selective activation of the mGlu(4) receptor alone could afford similar functional neuroprotection.EXPERIMENTAL APPROACHThe neuroprotective effects of 8 days of supranigral treatment with a positive allosteric modulator of mGlu(4) receptors, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl) cyclohexanecarboxylic acid (VU0155041), were investigated in rats with unilateral 6-hydroxydopamine lesions. The effects of VU0155041 treatment on motor function were assessed using both habitual (cylinder test) and forced (adjusted stepping, amphetamine-induced rotations) behavioural tests. Nigrostriatal tract integrity was examined by analysis of tyrosine hydroxylase, dopa decarboxylase or dopamine levels in the striatum and tyrosine hydroxylase-positive cell counts in the substantia nigra pars compacta.KEY RESULTSVU0155041 provided around 40% histological protection against a unilateral 6-hydroxydopamine lesion as well as significant preservation of motor function. These effects were inhibited by pre-treatment with (RS)-alpha-cyclopropyl-4-phosphonophenylglycine, confirming a receptor-mediated response. Reduced levels of inflammatory markers were also evident in the brains of VU0155041-treated animals.CONCLUSIONS AND IMPLICATIONSAllosteric potentiation of mGlu(4) receptors in the substantia nigra pars compacta provided neuroprotective effects in the 6-hydroxydopamine rat model A reduced inflammatory response may contribute, in part, to this action. In addition to the reported symptomatic effects, activation of mGlu(4) receptors may also offer a novel approach for slowing the progressive degeneration observed in Parkinson's disease.