The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain
The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain
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DOI：
10.1016/j.expneurol.2019.113062
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发表时间：
2020-01
影响因子：
5.3
通讯作者：
Sandy Stayte;Kathryn J. Laloli;Peggy Rentsch;A. Lowth;Kong M. Li;R. Pickford;B. Vissel
中科院分区：
文献类型：
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作者：
Sandy Stayte;Kathryn J. Laloli;Peggy Rentsch;A. Lowth;Kong M. Li;R. Pickford;B. Vissel
兴奋性神经递质谷氨酸在基底神经节运动回路中是必需的，长期以来被认为与帕金森病（PD）的细胞死亡和变性有关。虽然先前的研究表明NMDA和AMPA受体在兴奋性毒性和PD中都有重要作用，但对第三类嗜离子性谷氨酸受体，海碱盐受体的研究较少。考虑到盐酸盐受体亚基GluK1-GluK3在pd相关的关键脑区域的表达，有人认为GluK1-GluK3可能导致兴奋性毒性细胞损失。因此，本研究探讨了盐酸盐受体拮抗剂UBP310在PD动物模型中的神经保护作用。体视定量显示，在急性MPTP小鼠PD模型中，UBP310显著增加了黑质致密部多巴胺能和总神经元群的存活率。相比之下，UBP310无法挽救mptp诱导的纹状体多巴胺水平或多巴胺转运体表达的丧失。此外，在所有测量中，GluK1、GluK2或GluK3的缺失对MPTP或ubp310介导的效应没有影响。有趣的是，UBP310并没有减轻6-OHDA毒性引起的中脑细胞损失。这些结果表明UBP310对中脑MPTP神经毒性提供神经保护，而MPTP神经毒性不依赖于特定的盐酸盐受体亚基。
The excitatory neurotransmitter glutamate is essential in basal ganglia motor circuits and has long been thought to contribute to cell death and degeneration in Parkinson's disease (PD). While previous research has shown a significant role of NMDA and AMPA receptors in both excitotoxicity and PD, the third class of ionotropic glutamate receptors, kainate receptors, have been less well studied. Given the expression of kainate receptor subunits GluK1-GluK3 in key PD-related brain regions, it has been suggested that GluK1-GluK3 may contribute to excitotoxic cell loss. Therefore the neuroprotective potential of the kainate receptor antagonist UBP310 in animal models of PD was investigated in this study. Stereological quantification revealed administration of UBP310 significantly increased survival of dopaminergic and total neuron populations in the substantia nigra pars compacta in the acute MPTP mouse model of PD. In contrast, UBP310 was unable to rescue MPTP-induced loss of dopamine levels or dopamine transporter expression in the striatum. Furthermore, deletion of GluK1, GluK2 or GluK3 had no effect on MPTP or UBP310-mediated effects across all measures. Interestingly, UBP310 did not attenuate cell loss in the midbrain induced by intrastriatal 6-OHDA toxicity. These results indicate UBP310 provides neuroprotection in the midbrain against MPTP neurotoxicity that is not dependent on specific kainate receptor subunits.