| Autor: |
Li, Qiang, Sandoval, Alfredo, Moth, John, Shang, Junkui, Liew, Jia Yi, Dunn, Tiffany, Yang, Zhiyun, Su, Junfeng, Henwood, Melissa, Williams, Philip, Chen, Bo |
| Předmět: |
|
| Zdroj: |
Science Translational Medicine; 9/25/2024, Vol. 16 Issue 766, p1-14, 14p |
| Abstrakt: |
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. Editor's summary: Spinal neuron swelling occurs after spinal cord injury (SCI), but the mechanisms, dynamics, and relationship of neural swelling to long-term locomotor deficits remain unclear. Here, Li et al. visualized neuronal swelling after SCI in mice using whole-mount tissue and a three-dimensional image analysis pipeline. They found that both excitatory and inhibitory neurons undergo swelling and loss after SCI, but with differing kinetics. Targeting overall tissue edema did not reduce neuronal swelling; however, inhibition of the Na+-K+-Cl− cotransporter 1 (NKCC1) with the FDA-approved drug bumetanide reduced excitatory neuron swelling. Bumetanide given in the first 4 weeks after injury improved recovery of motor function in the presence of excitatory neurons. These findings in mice suggest that excitatory neuronal swelling may be a therapeutic target for reducing functional deficits after SCI. —Molly Ogle [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
