Comparative Medicine and Animal Resource Centre, McGill University, Montreal, QC, Canada.
Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, H3A 2B4, Canada.
Pharmacol Rep. 2022 Aug;74(4):614-625. doi: 10.1007/s43440-022-00378-9. Epub 2022 Jun 27.
We have previously demonstrated that the metabotropic glutamate 2 and 3 (mGlu) antagonist LY341495 reverses the anti-dyskinetic and anti-psychotic benefits conferred by mGlu activation and serotonin 2A (5-HT) antagonism. Here, we hypothesised that a higher dose of LY341495, associated with a higher antagonistic effect at mGlu receptors, would result in a reduction of the reversal of mGlu activation and 5-HT blockade on dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.
After induction of parkinsonism with MPTP, marmosets entered 3 streams of experiments, in which the following treatments were administered, in combination with l-3,4-dihydroxyphenylalanine (L-DOPA), after which dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were rated: 1. vehicle/vehicle, LY354740 (mGlu orthosteric agonist)/vehicle, LY354740/LY341495 1 mg/kg and LY354740/LY341495 3 mg/kg; 2. vehicle/vehicle, LY487379 (mGlu positive allosteric modulator)/vehicle, LY487379/LY341495 1 mg/kg and LY487379/LY341495 3 mg/kg; 3. vehicle/vehicle, EMD-281,014 (5-HT antagonist)/vehicle, EMD-281,014/LY341495 1 mg/kg and EMD-281,014/LY341495 3 mg/kg.
Each of LY354740, LY487379 and EMD-281,014 reduced the severity of L-DOPA-induced dyskinesia, by 55%, 39% and 40%, respectively (all p < 0.001), as well as the severity of PLBs, by 48%, 36% and 41%, respectively (all p < 0.001). Adding LY341495 1 and 3 mg/kg to each of LY354740, LY487379 and EMD-281,014 resulted in a dose-dependent reversal of their anti-dyskinetic and anti-psychotic actions. No effect on the anti-parkinsonian action of L-DOPA was noted with any treatment combination.
These results suggest that an antagonistic effect at mGlu receptors may not be sufficient to overcome the deleterious effect of mGlu blockade on dyskinesia in PD. It remains to be seen whether similar effects would have been obtained with a selective mGlu antagonist.
我们之前已经证明，代谢型谷氨酸 2 和 3（mGlu）拮抗剂 LY341495 可以逆转 mGlu 激活和 5-羟色胺 2A（5-HT）拮抗作用所带来的抗运动障碍和抗精神病作用。在这里，我们假设更高剂量的 LY341495，与 mGlu 受体的更高拮抗作用相关联，将导致 mGlu 激活和 5-HT 阻断对运动障碍的逆转减少，在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的狨猴中。
在 MPTP 诱导帕金森病后，狨猴进入 3 个实验流，在给予以下治疗后，结合 l-3,4-二羟苯丙氨酸（L-DOPA），对运动障碍、精神病样行为（PLB）和帕金森病进行评分：1. 载体/载体、LY354740（mGlu 正变构调节剂）/载体、LY354740/LY341495 1mg/kg 和 LY354740/LY341495 3mg/kg；2. 载体/载体、LY487379（mGlu 正变构调节剂）/载体、LY487379/LY341495 1mg/kg 和 LY487379/LY341495 3mg/kg；3. 载体/载体、EMD-281,014（5-HT 拮抗剂）/载体、EMD-281,014/LY341495 1mg/kg 和 EMD-281,014/LY341495 3mg/kg。
LY354740、LY487379 和 EMD-281,014 分别降低了 L-DOPA 诱导的运动障碍的严重程度，分别为 55%、39%和 40%（均 p<0.001），以及精神病样行为的严重程度，分别为 48%、36%和 41%（均 p<0.001）。向 LY354740、LY487379 和 EMD-281,014 中的每一种添加 LY341495 1 和 3mg/kg 导致其抗运动障碍和抗精神病作用呈剂量依赖性逆转。与任何治疗组合均未观察到对 L-DOPA 的抗帕金森病作用有影响。
这些结果表明，mGlu 受体的拮抗作用可能不足以克服 mGlu 阻断对 PD 运动障碍的有害影响。是否会与选择性 mGlu 拮抗剂获得类似的效果仍有待观察。
