Michalettos Georgios, Clausen Fredrik, Rostami Elham, Marklund Niklas
Department of Clinical Sciences Lund, Neurosurgery, Lund University, Lund, Sweden.
Department of Medical Sciences, Section of Neurosurgery, Uppsala University, Uppsala, Sweden.
Neurotherapeutics. 2025 Jan;22(1):e00472. doi: 10.1016/j.neurot.2024.e00472. Epub 2024 Oct 20.
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.
创伤性脑损伤（TBI）是发病和死亡的主要原因，在老年人中尤为如此。在过去几十年中，老年TBI患者的发病率急剧上升。高龄是TBI的一个非常不利的预后因素，并且缺乏药物治疗选择。我们在23月龄的雄性和雌性小鼠中使用了控制性皮质撞击（CCI）TBI模型，并分析了损伤后用7,8-二羟基黄酮（7,8-DHF）（一种脑源性神经营养因子（BDNF）模拟化合物）治疗对白质病理的影响。在CCI或假手术损伤后，小鼠在损伤后30分钟接受皮下注射7,8-DHF（5mg/kg），并在损伤后2、7或14天（dpi）处死以进行组织学和免疫荧光分析。用卢氏固蓝（LFB）/甲酚紫染色进行的组织学评估表明，在2和7dpi时，给予7,8-DHF可使白质组织得以保留，在所有研究时间点皮质组织损失无差异。用7,8-DHF治疗导致在2和7dpi时轴突肿胀减少，这通过SMI-31（神经丝重链）免疫荧光观察到，并且在损伤周围白质中2dpi时TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）/CC1阳性成熟少突胶质细胞数量减少。7,8-DHF未改变血小板衍生生长因子受体（PDGFRα）阳性少突胶质细胞祖细胞损伤后的增殖。我们的结果表明，7,8-DHF可以通过减轻老年小鼠脑TBI后轴突损伤和少突胶质细胞死亡来减轻白质病理。这些数据表明有必要进一步探索7,8-DHF的临床应用。
