Evidence map›Paper›PMID 41508250›Full record

ArticleActa neuropathologica communications2026

Mapping the secondary response to traumatic brain injury using spatial transcriptomics shows acute 4-aminopyridine treatment mitigates axonal and molecular pathology.

Genevieve M Sullivan, Kryslaine L Radomski, Shaoqiu He, Matthew D Wilkerson, Clifton L Dalgard, Camille Alba, Xiaomei Zi, Martin L Doughty, Regina C Armstrong

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Genevieve M SullivanDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Kryslaine L RadomskiDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Shaoqiu HeDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Matthew D WilkersonDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Clifton L DalgardDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Camille AlbaDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Xiaomei ZiDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Martin L DoughtyDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.
Regina C ArmstrongDepartment of Anatomy, Physiology and Genetics in the School of Medicine at the Uniformed Services University of the Health Sciences, Bethesda, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA. regina.armstrong@usuhs.edu.

Funding

Congressionally Directed Medical Research Programs W81XWH-21-2-0040Uniformed Services University of the Health Sciences HU0001-23-2-0071Uniformed Services University of the Health Sciences HU0012420045
6 · The paper itself

Abstract

Damage to long myelinated axons of white matter tracts is a hallmark pathology resulting from traumatic brain injury (TBI) forces and secondary injury processes. 4-aminopyridine (4-AP) is an FDA-approved Kv1 potassium channel inhibitor designed to mitigate axon dysfunction. We examined repurposing 4-AP as an acute TBI treatment using clinically-oriented neuropathology of axon damage combined with unbiased genome-wide spatial transcriptomics for comprehensive analysis of secondary injury processes. Adult male and female mice received a non-penetrating impact TBI with 4-AP (i.p., b.i.d) on days 1-7 post-injury. Along corpus callosum (CC) axons, TBI disrupted node of Ranvier domains, exposing the putative 4-AP target of mislocalized Kv1 channels (p < 0.005). Clinically reasonable 4-AP dosing (0.5 mg/kg) reduced nodal Nav1.6 channel loss (p < 0.05) and Caspr heminode formation (p < 0.005) after injury. Quantification of β-amyloid precursor protein immunolabeling showed significantly reduced CC axon damage at 4-AP doses of 0.5 mg/kg and 5 mg/kg (each p < 0.005). 4-AP safety, based on potential seizure risk after TBI, was unaltered with vehicle or 0.5 mg/kg 4-AP, while the 5 mg/kg dose induced seizure behavior in sham and TBI groups (p < 0.0001). Spatial transcriptomics mapped molecular signatures to tissue pathology. TBI increased axonal injury response genes in the CC and in motor and somatosensory cortex sites of CC projection neurons. TBI induced disease-associated glial phenotypes that mapped predominantly within the CC. TBI increased pathway expression for immune and vascular functions, neuron and glial cell signaling, and cellular dyshomeostasis, while reducing expression in myelination-related pathways. Gene expression analysis of 4-AP treatment (0.5 mg/kg) indicated potassium channel target engagement and increased neuroaxonal activity, along with dampened secondary injury responses. Collectively, these findings reveal underlying molecular pathology of the secondary injury response and advance 4-AP translation to reduce axon damage and stimulate activity-dependent repair after acute TBI.

Indexed as

4-AminopyridineAxonsBrain Injuries, TraumaticPotassium Channel BlockersAnimalsCorpus CallosumFemaleMaleMiceMice, Inbred C57BLSpatial Transcriptomics4-AminopyridinePotassium Channel Blockers4-aminopyridineAxon damageGenome-wide spatial transcriptomicsMyelinPotassium channelTraumatic brain injury

Identifiers

PMID41508250
PMCPMC12882205

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.