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Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury

Michalettos, Georgios LU ; Clausen, Fredrik LU ; Rostami, Elham and Marklund, Niklas LU orcid (2025) In Neurotherapeutics 22(1).
Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and... (More)

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
7,8-DHF, Axonal injury, High age, Oligodendroglia, Traumatic brain injury, White matter
in
Neurotherapeutics
volume
22
issue
1
article number
e00472
publisher
Springer
external identifiers
  • pmid:39428261
  • scopus:85206921759
ISSN
1933-7213
DOI
10.1016/j.neurot.2024.e00472
language
English
LU publication?
yes
id
3bf2a5ff-f9c4-4f0f-ae58-b3811513dab4
date added to LUP
2024-12-18 11:28:02
date last changed
2025-07-03 03:37:49
@article{3bf2a5ff-f9c4-4f0f-ae58-b3811513dab4,
  abstract     = {{<p>Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.</p>}},
  author       = {{Michalettos, Georgios and Clausen, Fredrik and Rostami, Elham and Marklund, Niklas}},
  issn         = {{1933-7213}},
  keywords     = {{7,8-DHF; Axonal injury; High age; Oligodendroglia; Traumatic brain injury; White matter}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Springer}},
  series       = {{Neurotherapeutics}},
  title        = {{Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury}},
  url          = {{http://dx.doi.org/10.1016/j.neurot.2024.e00472}},
  doi          = {{10.1016/j.neurot.2024.e00472}},
  volume       = {{22}},
  year         = {{2025}},
}