纹状体内注射 KN-93 可改善帕金森病大鼠模型中左旋多巴诱导的运动障碍。
Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson's disease.
机构信息
Department of Neurology, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
出版信息
Neuropsychiatr Dis Treat. 2013;9:1213-20. doi: 10.2147/NDT.S45422. Epub 2013 Aug 19.
BACKGROUND
Levodopa remains the most effective drug for the treatment of Parkinson's disease (PD). However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID), which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood.
METHODS
In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA) injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 μg, 2 μg, or 5 μg) prior to levodopa treatment. Abnormal involuntary movements (AIMs) scores and apomorphine-induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845) levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR).
RESULTS
We found that both 2 μg and 5 μg KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 μg) reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 μg) reduced the expression of Gad1 and Nur77 in PD rats.
CONCLUSION
These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats.
背景
左旋多巴仍然是治疗帕金森病（PD）最有效的药物。然而，长期的左旋多巴治疗与左旋多巴诱导的运动障碍（LID）的出现有关，这阻碍了其在 PD 治疗中的应用。LID 的机制尚未完全了解。先前的一项研究表明，Ca(2+)/钙调蛋白依赖性蛋白激酶 II（CaMKII）抑制剂 KN-93 可用于改善大鼠的 LID。然而，KN-93 作为抗运动障碍的作用机制尚不完全清楚。
方法
在本研究中，通过 6-羟多巴胺（OHDA）注射诱导 PD 大鼠模型。然后，在给予左旋多巴治疗之前，将不同剂量的 KN-93（1μg、2μg 或 5μg）立体定向注射到纹状体中。在 PD 大鼠中测量异常不自主运动（AIMs）评分和阿扑吗啡诱导的旋转。通过 Western blot 测定 GluR1 丝氨酸-845 磷酸化水平（pGluR1S845）。通过实时聚合酶链反应（PCR）测量 Arc 和 Penk 水平。
结果
我们发现，2μg 和 5μg KN-93 治疗均可降低左旋多巴引发的 PD 大鼠的 AIMs 评分，而不影响左旋多巴的抗帕金森作用。与行为分析一致，KN-93 治疗（2μg）降低了 PD 大鼠的 pGluR1S845 水平。此外，KN-93 治疗（2μg）降低了 PD 大鼠中 Gad1 和 Nur77 的表达。
结论
这些数据表明，通过抑制 PD 大鼠中 CaMKII 的激活，纹状体注射 KN-93 可通过降低 pGluR1S845 的表达来减少 LID 的表达，从而有利于减少 LID 的表达。pGluR1S845 的表达降低进一步降低了 PD 大鼠中 Gad1 和 Nur77 的表达。
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