Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA.
Department of Biomedical Sciences, Grand Valley State University, 1 Campus Dr., Allendale, MI 49401, USA.
Exp Neurol. 2023 Nov;369:114522. doi: 10.1016/j.expneurol.2023.114522. Epub 2023 Aug 26.
Dopamine depletion associated with parkinsonism induces plastic changes in striatal medium spiny neurons (MSN) that are maladaptive and associated with the emergence of the negative side-effect of standard treatment: the abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Prevention of MSN dendritic spine loss is hypothesized to diminish liability for LID in Parkinson's disease. Blockade of striatal CaV1.3 calcium channels can prevent spine loss and significantly diminish LID in parkinsonian rats. While pharmacological antagonism with FDA approved CaV1 L-type channel antagonist dihydropyridine (DHP) drugs (e.g, isradipine) are potentially antidyskinetic, pharmacologic limitations of current drugs may result in suboptimal efficacy. To provide optimal CaV1.3 antagonism, we investigated the ability of a dual pharmacological approach to more potently antagonize these channels. Specifically, quinpirole, a D2/D3-type dopamine receptor (D2/3R) agonist, has been demonstrated to significantly reduce calcium current activity at CaV1.3 channels in MSNs of rats by a mechanism distinct from DHPs. We hypothesized that dual inhibition of striatal CaV1.3 channels using the DHP drug isradipine combined with the D2/D3 dopamine receptor agonist quinpirole prior to, and in conjunction with, levodopa would be more effective at preventing structural modifications of dendritic spines and providing more stable LID prevention. For these proof-of-principle studies, rats with unilateral nigrostriatal lesions received daily administration of vehicle, isradipine, quinpirole, or isradipine + quinpirole prior to, and concurrent with, levodopa. Development of LID and morphological analysis of dendritic spines were assessed. Contrary to our hypothesis, quinpirole monotherapy was the most effective at reducing dyskinesia severity and preventing abnormal mushroom spine formation on MSNs, a structural phenomenon previously associated with LID. Notably, the antidyskinetic efficacy of quinpirole monotherapy was lost in the presence of isradipine co-treatment. These findings suggest that D2/D3 dopamine receptor agonists when given in combination with levodopa and initiated in early-stage Parkinson's disease may provide long-term protection against LID. The negative interaction of isradipine with quinpirole suggests a potential cautionary note for co-administration of these drugs in a clinical setting.
帕金森病引起的多巴胺耗竭会导致纹状体中型多棘神经元（MSN）发生适应性变化，这些变化是不良的，并与标准治疗的负面副作用（称为左旋多巴诱导的运动障碍（LID））的出现有关。预防 MSN 树突棘丢失被认为可以降低帕金森病患者发生 LID 的可能性。阻断纹状体 CaV1.3 钙通道可以防止棘突丢失，并显著减少帕金森大鼠的 LID。虽然用 FDA 批准的 CaV1 L 型通道拮抗剂二氢吡啶（DHP）药物（如异搏定）进行药理学拮抗具有潜在的抗运动障碍作用，但目前药物的药理学局限性可能导致疗效不理想。为了提供最佳的 CaV1.3 拮抗作用，我们研究了更有力地拮抗这些通道的双重药理学方法的能力。具体来说，一种 D2/D3 型多巴胺受体（D2/3R）激动剂喹吡罗，已被证明通过一种与 DHP 不同的机制，显著降低大鼠 MSN 中 CaV1.3 通道的钙电流活性。我们假设在给予左旋多巴之前和同时，使用 DHP 药物异搏定和 D2/D3 多巴胺受体激动剂喹吡罗双重抑制纹状体 CaV1.3 通道，将更有效地预防树突棘结构的改变，并提供更稳定的 LID 预防。对于这些原理验证研究，单侧黑质纹状体损伤的大鼠每天给予载体、异搏定、喹吡罗或异搏定+喹吡罗，然后给予左旋多巴。评估 LID 的发展和树突棘形态分析。与我们的假设相反，喹吡罗单药治疗是最有效的降低运动障碍严重程度和防止 MSN 上异常蘑菇状棘突形成的方法，这是一种与 LID 相关的结构现象。值得注意的是，当与异搏定共同治疗时，喹吡罗单药的抗运动障碍作用丧失。这些发现表明，当与左旋多巴联合使用并在帕金森病早期开始时，D2/D3 多巴胺受体激动剂可能提供长期的 LID 保护。异搏定与喹吡罗的负相互作用表明，在临床环境中联合使用这些药物时可能需要谨慎。
