Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice
Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice
复制标题
DOI：
10.1523/jneurosci.3831-03.2004
复制
发表时间：
2004-01-28
影响因子：
5.3
通讯作者：
Bruno, V
中科院分区：
文献类型：
--
作者：
Battaglia, G;Busceti, CL;Bruno, V
我们结合使用基因敲除小鼠和亚型选择性拮抗剂[2-甲基-6-（苯乙炔基）吡啶（MPEP）和（E）-2-甲基-6-（2-苯乙烯基）-吡啶（SIB 1893）]，以检查mGlu 5代谢型谷氨酸受体的内源性激活是否有助于1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）帕金森病模型中黑质-纹状体损伤的病理生理学。高剂量的MPTP（四次注射20 mg/kg，腹膜内，每2小时一次）诱导野生型小鼠的高死亡率和黑质-纹状体通路的几乎完全变性。mGlu 5基因敲除小鼠对MPTP毒性的敏感性较低，如较高的存活率和较轻的黑质纹状体损伤所示。在MPEP注射（5 mg/kg，i. p.，每次MPTP注射前30分钟）。在mGlu 5基因敲除小鼠中，MPEP治疗没有进一步增加对80 mg/kg MPTP的神经保护作用，表明该药物通过抑制mGlu 5受体起作用。在野生型小鼠中，当针对较低剂量的MPTP（30 mg/kg，单次注射，或10 mg/kg注射中的四次）进行攻击时，MPEP也具有神经保护作用。MPEP的作用被SIB 1893模拟，但不被mGlu 1受体拮抗剂7-羟基亚氨基环丙烷[B]色烯-1a-羧酸乙酯模拟。MPEP没有改变注射MPTP的小鼠纹状体中1-甲基-4-苯基吡啶离子形成的动力学。我们的结论是，mGlu 5受体作为放大器的MPTP毒性和mGlu 5受体拮抗剂可能会限制在帕金森氏症的实验模型中的黑质纹状体损伤的程度。
We combined the use of knock-out mice and subtype-selective antagonists [2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB1893)] to examine whether endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the pathophysiology of nigro-striatal damage in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. High doses of MPTP (four injections of 20 mg/kg, i.p., every 2 hr) induced a high mortality rate and a nearly total degeneration of the nigro-striatal pathway in wild-type mice. mGlu5 knock-out mice were less sensitive to MPTP toxicity, as shown by a higher survival and a milder nigro-striatal damage. Protection against MPTP (80 mg/kg) toxicity was also observed after MPEP injections (four injections of 5 mg/kg, i.p., 30 min before each MPTP injection). MPEP treatment did not further increase neuroprotection against 80 mg/kg of MPTP in mGlu5 knock-out mice, indicating that the drug acted by inhibiting mGlu5 receptors. In wild-type mice, MPEP was also neuroprotective when challenged against lower doses of MPTP (either 30 mg/kg, single injection, or four of 10 mg/kg injections). The action of MPEP was mimicked by SIB1893 but not by the mGlu1 receptor antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester. MPEP did not change the kinetics of 1-methyl-4-phenylpyridinium ion formation in the striatum of mice injected with MPTP. We conclude that mGlu5 receptors act as amplifiers of MPTP toxicity and that mGlu5 receptor antagonists may limit the extent of nigro-striatal damage in experimental models of parkinsonism.