NF-κB inhibition attenuates sympathetic hyperreflexia and concomitant development of autonomic dysreflexia and immune dysfunction after spinal cord injury

Micaela L. O'Reilly, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
Mariah J. Wulf, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
Theresa M. Connors, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
Ying Jin, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
Frank Bearoff, Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Nan Hai, School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA.
Julien Bouyer, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA.
Sandhya Kortagere, Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.
Yinghui Zhong, School of Biomedical Engineering Science and Health Systems, Drexel University, Philadelphia, PA, USA.
John R. Bethea, Department of Anatomy and Cell Biology, George Washington University, Washington, DC, USA.
Veronica J. Tom, Department of Neurobiology and Anatomy, Marion Murray Spinal Cord Research Center, Drexel University College of Medicine, Philadelphia, PA, USA. vjt25@drexel.edu.

Document Type

Journal Article

Publication Date

5-22-2025

Journal

Communications biology

Volume

8

Issue

1

DOI

10.1038/s42003-025-08237-y

Abstract

Heightened sympathetic reflexes (sympathetic hyperreflexia, SH) post-high-level spinal cord injury (SCI) detrimentally impact effector organs, resulting in peripheral immune dysfunction and cardiovascular disease, two leading causes of morbidity and mortality in SCI. We previously found that an activated neuroimmune system after SCI contributes to intraspinal plasticity in the spinal sympathetic reflex (SSR) circuit, underlying SH. We hypothesize that activation of NF-κB, a key regulator of inflammation, in spinal cord below-SCI contributes to driving SSR circuit plasticity, resulting in SH-associated autonomic dysreflexia (AD) and peripheral immune dysfunction. Here, we demonstrate inhibition of central NF-κB signaling via intrathecal delivery of dimethylamino parthenolide (DMAPT) significantly decreases SH post-complete transection of thoracic spinal segment 3 in adult rats. This included reduced AD severity that was associated with decreased interneuron recruitment into the SSR circuit after SCI. We also observed intrathecal DMAPT-treatment improved survival post-SCI that corresponded with normalized numbers of splenic regulatory T-cells. These findings underscore central NF-κB signaling as a key component driving SH after SCI.

Department

Anatomy and Regenerative Biology

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