我们先前已经发现,代谢型谷氨酸2型受体(mGluR2)的选择性激活和代谢型谷氨酸2型和3型受体(mGluR2/3)的同时刺激可增强L-3,4-二羟基苯丙氨酸的抗帕金森病作用(L-DOPA)。这里,我们试图确定mGluR2/3正构激动剂LY-354,740和LY-404,039的影响,以及mGluR2正变构调节剂LY-487,379和CBiPES对运动范围的影响,运动迟缓,姿势和警觉性作为L-DOPA的辅助手段。十个1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)损伤的the猴进入4个实验流:L-DOPALY-354,740(车辆,0.1、0.3和1mg/kg),L-DOPA+LY-404,039(车辆,0.1、1和10mg/kg),L-DOPA+LY-487,379(车辆,0.1、1和10mg/kg),L-DOPA+CBiPES(车辆,0.1、1和10mg/kg)。对于每个分子,治疗是随机的,和运动的范围,运动迟缓,姿势和警觉性由盲法评估员进行评估.所测试的化合物中没有一个显著改变了运动的全球范围。LY-404,039和CBiPES都减少了全球运动迟缓,高达46%(均P<0.05)。LY-354,740,LY-404,039和CBiPES各自将全球姿态提高了35%,44%和39%(各P<0.05),分别。LY-404,039和CBiPES的警觉性均提高了54%(P<0.05)和79%(P<0.01),分别。LY-487,379没有改善任何参数。我们的结果表明,选择性mGluR2正变构调节和联合mGluR2/3正构刺激可能有益于运动迟缓,当添加到L-DOPA时,PD的姿势和警觉性,这可能代表了通过这些机制起作用的分子的新治疗适应症。
We have previously discovered that the selective activation of metabotropic glutamate type 2 receptors (mGluR2) and concurrent stimulation of metabotropic glutamate types 2 and 3 receptors (mGluR2/3) enhance the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA). Here, we sought to determine the effects of the mGluR2/3 orthosteric agonists LY-354,740 and LY-404,039, as well as the effects of the mGluR2 positive allosteric modulators LY-487,379 and CBiPES on the range of movement, bradykinesia, posture and alertness as adjuncts to L-DOPA. Ten 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-lesioned marmosets entered 4 experimental streams: L-DOPA + LY-354,740 (vehicle, 0.1, 0.3 and 1 mg/kg), L-DOPA + LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + LY-487,379 (vehicle, 0.1, 1 and 10 mg/kg), L-DOPA + CBiPES (vehicle, 0.1, 1 and 10 mg/kg). For each molecule, treatments were randomised, and the range of movement, bradykinesia, posture and alertness were assessed by a blinded rater. None of the tested compounds significantly altered the global range of movement. LY-404,039 and CBiPES both reduced global bradykinesia, by up to 46% (both P < 0.05). LY-354,740, LY-404,039 and CBiPES each improved global posture by 35%, 44% and 39% (each P < 0.05), respectively. LY-404,039 and CBiPES both enhanced alertness by 54% (P < 0.05) and 79% (P < 0.01), respectively. LY-487,379 did not improve any of the parameters. Our results suggest that selective mGluR2 positive allosteric modulation and combined mGluR2/3 orthosteric stimulation might benefit bradykinesia, posture and alertness in PD when added to L-DOPA, which potentially represent novel therapeutic indications for molecules acting via these mechanisms.