Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury
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 use...
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Elsevier
2025-01-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924001594 |
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| author | Georgios Michalettos Fredrik Clausen Elham Rostami Niklas Marklund |
| author_facet | Georgios Michalettos Fredrik Clausen Elham Rostami Niklas Marklund |
| author_sort | Georgios Michalettos |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5efed48d983543b29ae85590b5a52027 |
| institution | Kabale University |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-5efed48d983543b29ae85590b5a520272025-02-01T04:11:51ZengElsevierNeurotherapeutics1878-74792025-01-01221e00472Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injuryGeorgios Michalettos0Fredrik Clausen1Elham Rostami2Niklas Marklund3Department of Clinical Sciences Lund, Neurosurgery, Lund University, Lund, SwedenDepartment of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, SwedenDepartment of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, Sweden; Department of Neuroscience, Karolinska Institute, Stockholm, SwedenDepartment of Clinical Sciences Lund, Neurosurgery, Lund University and Lund University Hospital, Lund, Sweden; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S1878747924001594Traumatic brain injuryHigh age7,8-DHFWhite matterOligodendrogliaAxonal injury |
| spellingShingle | Georgios Michalettos Fredrik Clausen Elham Rostami Niklas Marklund Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury Neurotherapeutics Traumatic brain injury High age 7,8-DHF White matter Oligodendroglia Axonal injury |
| title | Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| title_full | Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| title_fullStr | Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| title_full_unstemmed | Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| title_short | Post-injury treatment with 7,8-dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| title_sort | post injury treatment with 7 8 dihydroxyflavone attenuates white matter pathology in aged mice following focal traumatic brain injury |
| topic | Traumatic brain injury High age 7,8-DHF White matter Oligodendroglia Axonal injury |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924001594 |
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