Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada.
Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
Psychopharmacology (Berl). 2023 Oct;240(10):2093-2099. doi: 10.1007/s00213-023-06428-1. Epub 2023 Jul 29.
Positive allosteric modulation of metabotropic glutamate type 4 (mGlu) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD).
We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia.
Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured.
ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses.
Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu PAMs on PD psychosis.
代谢型谷氨酸受体 4（mGlu）的正变构调节是一种有希望的策略，可以减轻帕金森病的残疾和 L-3,4-二羟基苯丙氨酸（L-DOPA）引起的运动障碍。ADX-88178 是一种高度选择性的 mGlu 正变构调节剂（PAM），此前在帕金森病（PD）的 6-羟多巴胺损伤大鼠模型中增强了 L-DOPA 的抗帕金森作用。
我们试图探讨 ADX-88178 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的狨猴的类精神病行为（PLBs）的影响。我们还旨在确定 ADX-88178 对帕金森病和运动障碍的影响。
六只 MPTP 损伤的狨猴给予 L-DOPA 慢性治疗，以诱导稳定的 PLBs 和运动障碍。然后，他们以随机方式皮下给予 ADX-88178（0.01、0.1 和 1mg/kg）或载体，与 L-DOPA/苯丝肼（15/3.75mg/kg）联合使用。然后测量 PLBs、帕金森病和运动障碍。
ADX-88178 以 1mg/kg 的剂量轻度加重了整体 PLBs（增加 13%，P=0.020）。单独使用 L-DOPA 的有效时间为 158 分钟，而添加 ADX-88178 1mg/kg 后，有效时间为 212 分钟（增加 34%，P=0.011）。因此，ADX-88178 1mg/kg 降低了整体帕金森病残疾，降低了 38%（P=0.0096）。ADX-88178 1mg/kg 减少了峰剂量运动障碍的 34%（P=0.015）。较低剂量提供了最小的效果。
尽管这些结果提供了额外的证据表明 mGlu 正变构调节作为 L-DOPA 的辅助治疗对帕金森病的抗帕金森和抗运动障碍作用，但它们也表明 ADX-88178 可能会加重多巴胺能精神病。需要进一步的研究来评估 mGlu PAMs 对 PD 精神病的这种可能的不良影响。
