Yao Fen, Cai Shen-Quan, Cheng Hui-Xian, Ren Li-Wen, Hui Kang-Li, Liu Qing-Zhen, Guo Min, Chen Li-Hui, Qian Bin, Zeng Yang, Li Feng, Duan Man-Lin
Department of Anesthesiology, Nanjing Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Department of Anesthesiology, The First People's Hospital of Yancheng, Yancheng Clinical College of Xuzhou Medical University, Yancheng, Jiangsu, China.
Neurochem Res. 2025 Apr 3;50(2):134. doi: 10.1007/s11064-025-04383-1.
Cardiac arrest (CA) remains a leading cause of mortality and morbidity worldwide. Cognitive deficits are common neurological sequelae among CA survivors. Preclinical and clinical studies have confirmed that therapeutic hypothermia (TH) is an effective intervention for mitigating brain injury following CA. Hypothermia induces the expression of specific small proteins, including RNA-binding motif protein 3 (RBM3), which provides neuroprotection under stress conditions. However, the role of RBM3 in TH after CA has not been fully elucidated. In this study, we investigated the role of RBM3 in attenuating cognitive deficits following hypothermic brain resuscitation. We constructed a rat model of CA and resuscitation, and used shRNA transfection to interfere with RBM3 expression to explore the underlying mechanisms of TH's effects on cognitive alterations. Rats were randomly assigned to one of five groups: sham group (Sham), CA group (CA), TH group (TH), adeno-associated virus (AAV)-shRNA-RBM3 transfection group (shRNA-RBM3), and AAV-shRNA-negative control transfection group (shRNA-control). Key synaptic regulatory proteins, dendritic spines, and synaptic ultrastructures were examined. The rats exhibited spatial learning and memory impairments in the Morris water maze test and novel object recognition task. Hypothermia increased RBM3 expression in hippocampal neurons, mitigated early brain injury, preserved dendritic spine integrity and synaptic ultrastructure, upregulated key synaptic regulatory proteins, and ameliorated cognitive impairment following resuscitation. When RBM3 expression in the hippocampus was inhibited, the beneficial effects of therapeutic hypothermia were partially reversed. Overall, our findings provide new insights into the mechanisms of hypothermia-induced neuroprotection, demonstrating that neuroplasticity and rehabilitation can be achieved following global cerebral ischemia-reperfusion injury after CA. Therefore, the RBM3-mediated cold shock pathway represents a potential target for enhancing neuroprotection and neurorehabilitation through hypothermia.
心脏骤停（CA）仍是全球范围内导致死亡和发病的主要原因。认知缺陷是CA幸存者中常见的神经后遗症。临床前和临床研究已证实，治疗性低温（TH）是减轻CA后脑损伤的有效干预措施。低温诱导特定小蛋白的表达，包括RNA结合基序蛋白3（RBM3），其在应激条件下提供神经保护作用。然而，RBM3在CA后TH中的作用尚未完全阐明。在本研究中，我们调查了RBM3在减轻低温脑复苏后认知缺陷中的作用。我们构建了CA和复苏的大鼠模型，并使用短发夹RNA（shRNA）转染来干扰RBM3表达，以探索TH对认知改变影响的潜在机制。将大鼠随机分为五组之一：假手术组（Sham）、CA组（CA）、TH组（TH）、腺相关病毒（AAV）-shRNA-RBM3转染组（shRNA-RBM3）和AAV-shRNA阴性对照转染组（shRNA-control）。检测关键突触调节蛋白、树突棘和突触超微结构。在莫里斯水迷宫试验和新物体识别任务中，大鼠表现出空间学习和记忆障碍。低温增加了海马神经元中RBM3的表达，减轻了早期脑损伤，保留了树突棘完整性和突触超微结构，上调了关键突触调节蛋白，并改善了复苏后的认知障碍。当海马中RBM3表达受到抑制时，治疗性低温的有益作用部分被逆转。总体而言，我们的研究结果为低温诱导神经保护的机制提供了新的见解，表明在CA后的全脑缺血再灌注损伤后可以实现神经可塑性和康复。因此，RBM3介导的冷休克途径代表了通过低温增强神经保护和神经康复的潜在靶点。
