减少脊髓损伤后兴奋神经元的长期肿胀可改善小鼠的运动恢复

IF 15.8 1区 医学 Q1 CELL BIOLOGY Science Translational Medicine Pub Date : 2024-09-25 DOI:10.1126/scitranslmed.adn7095
Qiang Li, Alfredo Sandoval, John Moth, Junkui Shang, Jia Yi Liew, Tiffany Dunn, Zhiyun Yang, Junfeng Su, Melissa Henwood, Philip Williams, Bo Chen
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引用次数: 0

摘要

脊髓损伤(SCI)会导致急性损伤,并引发继发性损伤反应,造成持续的神经元损失和功能障碍。然而,这些迟发性神经元病变的内在机制尚未完全明了。脊髓损伤会导致脊髓神经元肿胀,但细胞肿胀对脊髓损伤后神经元丢失和功能障碍的影响尚未得到系统描述。在这项研究中,我们设计了一个三维图像分析管道来评估脊髓神经元,在双侧半切 SCI 小鼠模型中检查它们的类型、数量、体积和空间分布。我们发现,兴奋性神经元和抑制性神经元都会肿胀和丢失,但时间模式不同。抑制性神经元在脊髓损伤后第 2 天出现明显肿胀和数量下降,到第 14 天症状消失。相比之下,兴奋性神经元在小鼠脊髓损伤后至少 35 天内保持持续肿胀和细胞持续丢失。兴奋性神经元表现出Na+-K+-Cl-共转运体1(NKCC1)的持续表达,而抑制性神经元在脊髓损伤后第14天时则出现蛋白下调。使用食品和药物管理局批准的NKCC1抑制剂布美他尼减轻了兴奋性神经元的肿胀,并减少了它们在脊髓损伤后继发性损伤阶段的损失。小鼠在脊髓损伤后服用布美他尼改善了运动功能的恢复,而且在停止治疗后,其功能益处至少还能持续4周。这项研究加深了我们对脊髓损伤相关病理的了解,并将布美他尼作为一种潜在的治疗方法,用于缓解脊髓损伤后神经元的持续肿胀并促进恢复。
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Reduction of prolonged excitatory neuron swelling after spinal cord injury improves locomotor recovery in mice
Spinal cord injury (SCI) results in acute damage and triggers secondary injury responses with sustained neuronal loss and dysfunction. However, the underlying mechanisms for these delayed neuronal pathologies are not entirely understood. SCI results in the swelling of spinal neurons, but the contribution of cell swelling to neuronal loss and functional deficits after SCI has not been systematically characterized. In this study, we devised a three-dimensional image analysis pipeline to evaluate spinal neurons, examining their types, quantities, volumes, and spatial distribution in a double-lateral hemisection SCI mouse model. We found that both excitatory and inhibitory neurons swell and are lost, albeit with distinct temporal patterns. Inhibitory neurons demonstrated marked swelling and decline in number on day 2 after SCI, which resolved by day 14. In contrast, excitatory neurons maintained persistent swelling and continued cell loss for at least 35 days after SCI in mice. Excitatory neurons exhibited sustained expression of the Na+-K+-Cl cotransporter 1 (NKCC1), whereas inhibitory neurons down-regulated the protein by day 14 after SCI. Treatment with a Food and Drug Administration–approved NKCC1 inhibitor, bumetanide, mitigated swelling of excitatory neurons and reduced their loss in the secondary injury phase after SCI. The administration of bumetanide after SCI in mouse improved locomotor recovery, with functional benefits persisting for at least 4 weeks after treatment cessation. This study advances our understanding of SCI-related pathology and introduces bumetanide as a potential treatment to mitigate sustained neuronal swelling and enhance recovery after SCI.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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