Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Department of Biomedical Sciences, Cagliari University, Cagliari, Italy.
J Parkinsons Dis. 2020;10(4):1503-1514. doi: 10.3233/JPD-202061.
We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID.
We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists.
Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum.
BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2.
Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1-D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.
我们最近表明，腺相关病毒（AAV）载体介导的纹状体脑源性神经营养因子（BDNF）过表达加重了 6-羟多巴胺（6-OHDA）损伤大鼠的左旋多巴诱导的异动症（LID）。这种效应伴随着纹状体 5-羟色胺能末梢的广泛发芽，这解释了 LID 易感性增加的原因。
我们旨在研究 BDNF 的作用是否仅限于 LID，还是扩展到直接 D1 受体激动剂诱导的异动症。
单侧 6-OHDA 损伤大鼠接受 AAV 载体注射以诱导 BDNF 或 GFP 过表达。8 周后，动物每天接受低剂量 SKF82958（0.02mg/kg sc）治疗，并评估异动症的发生。实验结束时，测量纹状体中 D1 和 D3 受体表达水平和 D1 受体依赖性信号通路。
与 GFP 组相比，BDNF 过表达显著加重了 SKF82958 诱导的异动症，并增加了纹状体水平的 D3 受体表达，即使在没有药物治疗的情况下也是如此；相比之下，D1 受体水平不受影响。在 BDNF 过表达纹状体中，SKF82958 给药导致 D1-D3 受体共免疫沉淀水平增加和 Thr34 DARPP-32 和 ERK1/2 的磷酸化水平增加。
在这里，我们提供了证据表明 BDNF、D3 受体和 D1-D3 受体在 6-OHDA 损伤大鼠异动症易感性增加中的功能联系。我们认为 D1-D3 受体相互作用可能是导致异动症出现的分子改变的关键；其破坏可能是治疗 PD 患者异动症的一种治疗策略。
