Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Neonatology. 2022;119(3):354-360. doi: 10.1159/000524207. Epub 2022 Apr 27.
Striatal neurons of term newborns are highly vulnerable to hypoxia-ischemia (H-I). In a piglet model of H-I, a dopamine D1 receptor antagonist and an adenosine A2A receptor antagonist alone preferentially protect striatonigral and striatopallidal neurons, respectively. Here, we tested the hypothesis whether the combined treatment with SCH23390, a D1 receptor antagonist, and SCH58261, an A2A receptor antagonist, is more efficacious than individual D1 and A2A receptor antagonist treatment.
Anesthetized newborn piglets were subjected to sham operation (n = 6) or 40 min of hypoxia and 7 min of airway occlusion. At 5 min of reoxygenation, piglets received the vehicle, SCH23390, SCH58261, or the combined treatment (n = 9 in each group). At 4 days of recovery, the number of viable neurons in the entire putamen was estimated by unbiased stereology.
Stereological results showed that sham-operated piglets had an estimated 2.9 × 106 neurons in the putamen, and the number of viable neurons in hypoxic-ischemic piglets was significantly reduced by 80% to 0.6 × 106/putamen. Treatment with SCH23390, SCH58261, and the combination increased the numbers of viable neurons to 1.4 × 106/putamen, 1.4 × 106/putamen, and 2.1 × 106/putamen, respectively. Notably, the combined treatment improved neuroprotection compared to individual therapy.
We conclude that simultaneous inhibition of dopamine D1 receptors and adenosine A2A receptors saves more neurons than individual treatment in the highly vulnerable putamen of a large-animal neonatal H-I model.
足月新生儿纹状体神经元极易受到缺氧缺血（H-I）的影响。在新生猪 H-I 模型中，单独使用多巴胺 D1 受体拮抗剂和腺苷 A2A 受体拮抗剂分别优先保护纹状体苍白球和纹状体黑质神经元。在这里，我们测试了一个假设，即联合使用 SCH23390（一种 D1 受体拮抗剂）和 SCH58261（一种 A2A 受体拮抗剂）的治疗效果是否优于单独使用 D1 和 A2A 受体拮抗剂的治疗效果。
麻醉新生仔猪接受假手术（n=6）或 40 分钟缺氧和 7 分钟气道阻塞。复氧 5 分钟时，仔猪接受载体、SCH23390、SCH58261 或联合治疗（每组 n=9）。在恢复的第 4 天，通过无偏立体学估计整个壳核中存活神经元的数量。
立体学结果显示，假手术仔猪壳核中估计有 2.9×106 个神经元，缺氧缺血仔猪壳核中存活神经元数量显著减少 80%，至 0.6×106/壳核。用 SCH23390、SCH58261 和联合治疗分别使存活神经元的数量增加到 1.4×106/壳核、1.4×106/壳核和 2.1×106/壳核。值得注意的是，联合治疗比单独治疗更能改善神经保护作用。
我们得出结论，在大型动物新生 H-I 模型中，纹状体极易受到影响的情况下，同时抑制多巴胺 D1 受体和腺苷 A2A 受体比单独治疗能挽救更多的神经元。
