NKCC1 inhibition reduces periaxonal swelling, increases white matter sparing, and improves neurological recovery after contusive SCI.

Autor: Ames S; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Brooks J; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Jones E; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Morehouse J; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Cortez-Thomas F; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202; Bioengineering, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Desta D; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202., Stirling DP; Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, KY, USA 40202; Departments of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY, USA 40202; Anatomical Sciences and Neurobiology, University of Louisville, School of Medicine, Louisville, KY, USA 40202. Electronic address: david.stirling@louisville.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Sep; Vol. 199, pp. 106611. Date of Electronic Publication: 2024 Jul 18.
DOI: 10.1016/j.nbd.2024.106611
Abstrakt: Ultrastructural studies of contusive spinal cord injury (SCI) in mammals have shown that the most prominent acute changes in white matter are periaxonal swelling and separation of myelin away from their axon, axonal swelling, and axonal spheroid formation. However, the underlying cellular and molecular mechanisms that cause periaxonal swelling and the functional consequences are poorly understood. We hypothesized that periaxonal swelling and loss of connectivity between the axo-myelinic interface impedes neurological recovery by disrupting conduction velocity, and glial to axonal trophic support resulting in axonal swelling and spheroid formation. Utilizing in vivo longitudinal imaging of Thy1YFP + axons and myelin labeled with Nile red, we reveal that periaxonal swelling significantly increases acutely following a contusive SCI (T13, 30 kdyn, IH Impactor) versus baseline recordings (laminectomy only) and often precedes axonal spheroid formation. In addition, using longitudinal imaging to determine the fate of myelinated fibers acutely after SCI, we show that ∼73% of myelinated fibers present with periaxonal swelling at 1 h post SCI and ∼ 51% of those fibers transition to axonal spheroids by 4 h post SCI. Next, we assessed whether cation-chloride cotransporters present within the internode contributed to periaxonal swelling and whether their modulation would increase white matter sparing and improve neurological recovery following a moderate contusive SCI (T9, 50 kdyn). Mechanistically, activation of the cation-chloride cotransporter KCC2 did not improve neurological recovery and acute axonal survival, but did improve chronic tissue sparing. In distinction, the NKKC1 antagonist bumetanide improved neurological recovery, tissue sparing, and axonal survival, in part through preventing periaxonal swelling and disruption of the axo-myelinic interface. Collectively, these data reveal a novel neuroprotective target to prevent periaxonal swelling and improve neurological recovery after SCI.
Competing Interests: Declaration of competing interest The authors declare no competing financial interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: