Pharmacological and Drug Safety Research, Gedeon Richter Plc., POB: 27, Budapest 10, H-1475 , Hungary.
Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Essen, Germany.
Sci Rep. 2021 May 25;11(1):10873. doi: 10.1038/s41598-021-90273-9.
During preclinical drug testing, the systemic administration of scopolamine (SCO), a cholinergic antagonist, is widely used. However, it suffers important limitations, like non-specific behavioural effects partly due to its peripheral side-effects. Therefore, neuroimaging measures would enhance its translational value. To this end, in Wistar rats, we measured whisker-stimulation induced functional MRI activation after SCO, peripherally acting butylscopolamine (BSCO), or saline administration in a cross-over design. Besides the commonly used gradient-echo echo-planar imaging (GE EPI), we also used an arterial spin labeling method in isoflurane anesthesia. With the GE EPI measurement, SCO decreased the evoked BOLD response in the barrel cortex (BC), while BSCO increased it in the anterior cingulate cortex. In a second experiment, we used GE EPI and spin-echo (SE) EPI sequences in a combined (isoflurane + i.p. dexmedetomidine) anesthesia to account for anesthesia-effects. Here, we also examined the effect of donepezil. In the combined anesthesia, with the GE EPI, SCO decreased the activation in the BC and the inferior colliculus (IC). BSCO reduced the response merely in the IC. Our results revealed that SCO attenuated the evoked BOLD activation in the BC as a probable central effect in both experiments. The likely peripheral vascular actions of SCO with the given fMRI sequences depended on the type of anesthesia or its dose.
在临床前药物测试期间，广泛使用胆碱能拮抗剂东莨菪碱（SCO）进行系统给药。然而，它存在重要的局限性，例如非特异性行为效应，部分原因是其外周副作用。因此，神经影像学测量将提高其转化价值。为此，在 Wistar 大鼠中，我们在交叉设计中测量了 SCO、外周作用的丁基东莨菪碱（BSCO）或盐水给药后，胡须刺激引起的功能 MRI 激活。除了常用的梯度回波回波平面成像（GE EPI）外，我们还在异氟烷麻醉中使用了动脉自旋标记方法。使用 GE EPI 测量，SCO 降低了纹状体皮层（BC）中的诱发 BOLD 反应，而 BSCO 则增加了前扣带皮层的反应。在第二个实验中，我们在异氟烷+腹腔注射右美托咪定的组合麻醉中使用了 GE EPI 和自旋回波（SE）EPI 序列，以解释麻醉效应。在这里，我们还检查了多奈哌齐的效果。在组合麻醉中，使用 GE EPI，SCO 降低了 BC 和下丘脑中的激活。BSCO 仅降低了 IC 中的反应。我们的结果表明，SCO 在两个实验中都可能通过中枢作用减弱了 BC 中的诱发 BOLD 激活。在给定的 fMRI 序列中，SCO 的可能外周血管作用取决于麻醉类型或其剂量。
