CR-ICM, UMR-S975, Université Pierre et Marie Curie-Paris 6, Paris, France, INSERM, U975, Paris, France.
J Neurosci. 2013 Jul 17;33(29):11986-93. doi: 10.1523/JNEUROSCI.1568-13.2013.
Gait and balance disorders unresponsive to dopaminergic drugs in Parkinson's disease (PD) are secondary to lesions located outside the dopaminergic system. However, available animal models of PD fail to display l-3,4-dihydroxyphenylalanine (DOPA)-responsive parkinsonism and drug-resistant gait and balance disorders, and this lack of appropriate model could account for the deficit of efficient treatments. Because the pedunculopontine nucleus (PPN) plays an important role in locomotion control, we conducted the present study to investigate the consequences of combined dopaminergic and PPN lesions in a same animal. We used macaques that received first 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to render them parkinsonian and then local stereotaxic lesion of the PPN. Adding bilateral PPN lesions in MPTP-lesioned macaques induced dopamine-resistant gait and balance disorders but unexpectedly improved hypokinesia. Additional MPTP injections resulted in the association of a severe DOPA-responsive parkinsonism together with DOPA-unresponsive gait disorders. Histological examination assessed a severe dopaminergic degeneration and a significant loss of PPN cholinergic neurons. We observed similar results in aged monkeys intoxicated with MPTP: they developed severe DOPA-responsive hypokinesia and tremor together with unresponsive gait and balance disorders and displayed dopaminergic lesion and a weak but significant cholinergic PPN lesion. Our results highlight the complex role of the cholinergic PPN neurons in the pathophysiology of PD because its lesion induces a dual effect with an improvement of hypokinesia contrasting with a worsening of DOPA-unresponsive gait and balance disorders. Thus, we obtained a primate model of PD that could be useful to test symptomatic treatments for these heavily disabling symptoms.
帕金森病（PD）中对多巴胺能药物无反应的步态和平衡障碍继发于多巴胺能系统以外的病变。然而，现有的 PD 动物模型不能显示 l-3,4-二羟苯丙氨酸（DOPA）反应性帕金森病和耐药性步态和平衡障碍，这种缺乏适当模型的情况可能导致治疗效果不佳。由于脑桥被盖核（PPN）在运动控制中起重要作用，我们进行了本研究以调查同一动物中多巴胺能和 PPN 联合损伤的后果。我们使用首先接受 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒的猕猴使其患上帕金森病，然后对 PPN 进行局部立体定向损伤。在 MPTP 损伤的猕猴中双侧 PPN 损伤会导致多巴胺耐药性步态和平衡障碍，但出人意料地改善了运动迟缓。额外的 MPTP 注射导致严重的 DOPA 反应性帕金森病与 DOPA 无反应性步态障碍的关联。组织学检查评估了严重的多巴胺能变性和 PPN 胆碱能神经元的显著丧失。我们在 MPTP 中毒的老年猕猴中观察到了类似的结果：它们出现了严重的 DOPA 反应性运动迟缓、震颤以及无反应性步态和平衡障碍，同时显示出多巴胺能损伤和 PPN 胆碱能神经元的微弱但显著缺失。我们的结果突出了 PPN 胆碱能神经元在 PD 病理生理学中的复杂作用，因为其损伤会产生双重影响，一方面改善运动迟缓，另一方面恶化 DOPA 无反应性步态和平衡障碍。因此，我们获得了一种 PD 的灵长类动物模型，可能有助于测试这些严重致残症状的对症治疗方法。
