Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys
Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys
复制标题
DOI：
10.1093/brain/awr137
复制
发表时间：
2011-07-01
期刊：
影响因子：
14.5
通讯作者：
Smith, Yoland
中科院分区：
文献类型：
--
作者：
Masilamoni, Gunasingh J.;Bogenpohl, James W.;Smith, Yoland
黑质纹状体多巴胺能系统和蓝斑去甲肾上腺素能神经元的变性是帕金森病的重要病理特征。迫切需要开发减缓帕金森病神经变性进展的疗法。在本研究中，我们测试了是否高度特异性的代谢型谷氨酸受体5拮抗剂，3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶，减少多巴胺能和去甲肾上腺素能神经元的损失，使帕金森病猴慢性治疗低剂量的1-甲基-4-苯基-1，2，3，6-四氢吡啶。每周肌肉注射1-甲基-4-苯基-1，2，3，6-四氢吡啶（0.2-0.5 mg/kg体重），与每日给予3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶或载体，直至两个实验组中的任一个出现帕金森病运动症状（1-甲基-4-苯基-1，2，3，6-四氢吡啶/3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶与1-甲基-4-苯基-1，2，3，6-四氢吡啶/溶剂）。1-甲基-4-苯基-1，2，3，6-四氢吡啶给药21周后，所有1-甲基-4-苯基-1，2，3，6-四氢吡啶/溶剂给药动物均显示出帕金森病症状，而1-甲基-4-苯基-1，2，3，6-四氢吡啶/3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶给药猴均未受到显著影响。这些行为观察结果与体内正电子发射断层扫描多巴胺转运蛋白成像数据、中脑多巴胺能神经元的死后体视学计数以及多巴胺转运蛋白和酪氨酸羟化酶免疫反应性的纹状体强度测量结果一致，在1-甲基-4-苯基-1，2，3，6-四氢吡啶/3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶处理的动物中比在1-甲基-4-苯基-1，2，3，6-四氢吡啶/溶剂处理的猴中更显著。3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶处理对蓝斑和相邻的A5和A7去甲肾上腺素细胞群中1-甲基-4-苯基-1，2，3，6-四氢吡啶诱导的去甲肾上腺素神经元损失也有显著影响。在1-甲基-4-苯基-1，2，3，6-四氢吡啶/溶剂处理的动物中，在蓝斑/A5/A7去甲肾上腺素细胞组中发现几乎40%的酪氨酸羟化酶阳性去甲肾上腺素神经元损失，而在1-甲基-4-苯基-1，2，3，6-四氢吡啶/3-[2，3，6]-四氢吡啶/溶剂处理的动物中，神经元损失的程度低于对照值的15%。（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶处理的猴。我们的数据表明，慢性治疗的代谢型谷氨酸受体5拮抗剂，3-[（2-甲基-1，3-噻唑-4-基）乙炔基]吡啶，显着降低1-甲基-4-苯基-1，2，3，6-四氢吡啶对多巴胺能和去甲肾上腺素能细胞群在非人灵长类动物的毒性。这表明，代谢型谷氨酸受体5拮抗剂的使用可能是一个有用的策略，以减少帕金森病中的儿茶酚胺能神经元的变性。
Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease.