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@ARTICLE{Hubertus:276804,
author = {Hubertus, Vanessa and Meyer, Lea and Waldmann, Lilly and
Roolfs, Laurens and Taheri, Nima and Kersting, Katharina and
von Bronewski, Emily and Nieminen-Kelhä, Melina and
Kremenetskaia, Irina and Uhl, Christian and Fiedler, Kim C
and Ode, Jan-Erik and Rex, Andre and Prüß, Harald and
Rakhymzhan, Asylkhan and Hauser, Anja E and Niesner, Raluca
and Heppner, Frank L and Fehlings, Michael G and Vajkoczy,
Peter},
title = {{I}dentification of a {T}herapeutic {W}indow for
{N}eurovascular {U}nit {R}epair after {E}xperimental
{S}pinal {C}ord {I}njury.},
journal = {Journal of neurotrauma},
volume = {42},
number = {3-4},
issn = {0897-7151},
address = {Larchmont, NY},
publisher = {Liebert},
reportid = {DZNE-2025-00329},
pages = {212 - 228},
year = {2025},
abstract = {Traumatic spinal cord injury (SCI) is a devastating
condition for which effective neuroregenerative and
neuroreparative strategies are lacking. The post-traumatic
disruption of the blood-spinal cord barrier (BSCB) as part
of the neurovascular unit (NVU) is one major factor in the
complex pathophysiology of SCI, which is associated with
edema, inflammation, and cell death in the penumbra regions
of the spinal cord adjacent to the lesion epicenter. Thus,
the preservation of an intact NVU and vascular integrity to
facilitate the regenerative capacity following SCI is a
desirable therapeutic target. This study aims to identify a
therapeutic window of opportunity for NVU repair after SCI
by characterizing the timeframe of its post-traumatic
disintegration and reintegration with implications for
functional spinal cord recovery. Following thoracic
clip-compression SCI or sham injury, adult C57BL/6J mice
were followed up from one to 28 days. At one, three, seven,
14, and 28 days after SCI/sham, seven-Tesla magnetic
resonance imaging (MRI), neurobehavioral analysis (Basso
mouse scale, Tally subscore, CatWalk® gait analysis), and
following sacrifice immunohistochemistry were performed,
assessing vessel permeability via Evans blue (EVB)
extravasation, (functional) vessel density, and NVU
integrity. Thy1-yellow fluorescent protein+ mice were
additionally implanted with a customized spinal window
chamber and received longitudinal in vivo two-photon
excitation imaging (2PM) with the injection of
rhodamine-B-isothiocyanate-dextran for the combined imaging
of axons and vasculature up to 14 days after SCI/sham
injury. Post-traumatic edema formation as assessed by MRI
volumetry peaked at one to three days after injury, while
EVB permeability quantification revealed a thoroughly
injured BSCB up to 14 days after SCI. Partial regeneration
of functional vasculature via endogenous revascularization
was detected after one to four weeks, however, with only
$50-54\%$ of existing vessels regaining functional
perfusion. Longitudinal in vivo 2PM visualized the
progressive degeneration of initially preserved spinal cord
axons in the peri-traumatic zone after SCI while displaying
a rarefication of functionally perfused vessels up to two
weeks after injury. Neurobehavioral recovery started after
one week but remained impaired over the whole observation
period of four weeks after SCI. With this study, a
therapeutic window to address the impaired NVU starting from
the first days to two weeks after SCI is identified. A
number of lines of evidence including in vivo 2PM,
assessment of NVU integrity, and neurobehavioral assessments
point to the critical nature of targeting the NVU to enhance
axonal preservation and regeneration after SCI. Continuous
multifactorial therapy applications targeting the integrity
of the NVU over the identified therapeutic window of
opportunity appears promising to ameliorate functional
vessel perseverance and the spinal cord's regenerative
capacity.},
keywords = {Spinal Cord Injuries: physiopathology / Spinal Cord
Injuries: diagnostic imaging / Animals / Mice / Mice, Inbred
C57BL / Recovery of Function: physiology / Female / Disease
Models, Animal / Magnetic Resonance Imaging / Nerve
Regeneration: physiology / Time Factors / neurovascular unit
(Other) / spinal cord injury (Other) / spinal cord
regeneration (Other) / vascular injury (Other) / vascular
regeneration (Other)},
cin = {AG Prüß / AG Heppner},
ddc = {610},
cid = {I:(DE-2719)1810003 / I:(DE-2719)1810007},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39585767},
doi = {10.1089/neu.2024.0233},
url = {https://pub.dzne.de/record/276804},
}