Street Amaya L, Thakkar Vedant P, Lemke Sean W, Schoenbeck Liza M, Schumacher Kevin M, Sathyanesan Monica, Newton Samuel S, Kloth Alexander D
Department of Biology, Augustana University, Sioux Falls, SD 57197, USA.
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.
NeuroSci. 2025 Mar 12;6(1):25. doi: 10.3390/neurosci6010025.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects over 2% of the population worldwide and is characterized by repetitive behaviors, restricted areas of interest, deficits in social communication, and high levels of anxiety. Currently, there are no known effective treatments for the core features of ASD. The previous literature has established erythropoietin (EPO) as a promising antidepressant, working as a potent neurogenic and neurotrophic agent with hematopoietic side effects. Carbamoylated erythropoietin (CEPO), a chemically engineered non-hematopoietic derivative of EPO, appears to retain the neuroprotective factors of EPO without the hematologic properties. Recent evidence shows that CEPO corrects stress-related depressive behaviors in BALB/cJ (BALB) mice, which also have face validity as an ASD mouse model. We investigated whether CEPO can recover deficient social and anxiety-related behavioral deficits compared to C57BL/6J controls. After administering CEPO (40 μg/kg in phosphate-buffered saline) or vehicle over 21 days, we analyzed the mice's performance in the three-chamber social approach, the open field, the elevated plus maze, and the Porsolt's forced swim tasks. CEPO appeared to correct sociability in the three-chamber social approach task to C57 levels, increasing the amount of time the mice interacted with novel, social mice overall rather than altering the overall amount of exploratory activity in the maze. Consistent with this finding, there was no concomitant increase in the distance traveled in the open field, nor were there any alterations in the anxiety-related measures in the task. On the other hand, CEPO administration improved exploratory behavior in the elevated plus maze. This study marks the first demonstration of the benefits of a non-erythropoietic EPO derivative for social behavior in a mouse model of autism and merits further investigation into the mechanisms by which this action occurs.
自闭症谱系障碍（ASD）是一种神经发育障碍，影响着全球超过2%的人口，其特征包括重复行为、兴趣范围受限、社交沟通缺陷以及高度焦虑。目前，尚无已知有效的治疗方法来应对ASD的核心特征。先前的文献已将促红细胞生成素（EPO）确立为一种有前景的抗抑郁药，它作为一种强效的神经源性和神经营养剂，具有造血副作用。氨甲酰化促红细胞生成素（CEPO）是EPO的一种化学工程改造的非造血衍生物，似乎保留了EPO的神经保护因子而没有血液学特性。最近的证据表明，CEPO可纠正BALB/cJ（BALB）小鼠与应激相关的抑郁行为，而该小鼠作为ASD小鼠模型也具有表面效度。我们研究了与C57BL/6J对照组相比，CEPO是否能恢复社交和焦虑相关的行为缺陷。在21天内给予CEPO（40μg/kg溶解于磷酸盐缓冲盐水中）或赋形剂后，我们分析了小鼠在三室社交接近试验、旷场试验、高架十字迷宫试验和波索尔特强迫游泳试验中的表现。在三室社交接近试验中，CEPO似乎将社交能力纠正到了C57水平，增加了小鼠与新奇的社交小鼠总体互动的时间，而不是改变其在迷宫中的总体探索活动量。与这一发现一致的是，在旷场试验中行进的距离没有相应增加，且该试验中与焦虑相关的指标也没有任何改变。另一方面，给予CEPO改善了小鼠在高架十字迷宫中的探索行为。这项研究首次证明了非促红细胞生成素EPO衍生物对自闭症小鼠模型社交行为的益处，值得进一步研究这种作用发生的机制。
