Leikas Juuso V, Kohtala Samuel, Theilmann Wiebke, Jalkanen Aaro J, Forsberg Markus M, Rantamäki Tomi
School of Pharmacy (Pharmacology), University of Eastern Finland, Kuopio, Finland.
Laboratory of Neurotherapeutics, Division of Physiology and Neuroscience, Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
J Neurochem. 2017 Aug;142(3):456-463. doi: 10.1111/jnc.14066. Epub 2017 Jun 14.
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3β (GSK3β) and neurodegene-rative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3β inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3β within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3β signaling in naïve rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3β at the inhibitory Ser9 residue, and induced phosphorylation of AKT (protein kinase B; negative regulator of GSK3β) in the striatum of naïve rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.
帕金森病（PD）是一种进行性神经退行性运动障碍，主要影响黑质纹状体多巴胺能系统。糖原合酶激酶3β（GSK3β）活性增强与神经退行性过程之间的联系，促使人们对新型GSK3β抑制剂在PD实验模型中的潜在疾病修饰作用进行研究。因此，几种麻醉剂能够轻易抑制皮质和海马体中的GSK3β，这一有趣的能力促使我们研究短暂异氟烷麻醉对未处理大鼠和早期PD大鼠模型纹状体GSK3β信号传导的影响。深度但短暂（20分钟）的异氟烷麻醉暴露增加了未处理大鼠和单侧纹状体6-羟基多巴胺（6-OHDA）损伤大鼠纹状体中GSK3β在抑制性丝氨酸9位点的磷酸化，并诱导了AKT（蛋白激酶B；GSK3β的负调节因子）的磷酸化。6-OHDA方案导致黑质纹状体通路逐渐出现功能缺陷，表现为在6-OHDA注射后2周，动物更倾向于使用损伤纹状体同侧的肢体。有趣的是，在接受连续四次异氟烷治疗的动物中未观察到这种运动障碍（每48小时进行20分钟麻醉；治疗在6-OHDA注射后7天开始）。然而，异氟烷对纹状体或黑质酪氨酸羟化酶（多巴胺能神经元的标志物）蛋白水平没有影响。这一简短报告为麻醉剂在PD实验模型中的治疗潜力和神经生物学机制提供了有前景的结果，并为新型疾病修饰疗法的开发提供了指导。
