Wang Jing, Lu Yujiao, Carr Christopher, Dhandapani Krishnan M, Brann Darrell W
Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Front Neurosci. 2023 Jul 27;17:1227705. doi: 10.3389/fnins.2023.1227705. eCollection 2023.
Chronic neuroinflammation can exist for months to years following traumatic brain injury (TBI), although the underlying mechanisms remain poorly understood.
In the current study, we used a controlled cortical impact mouse model of TBI to examine whether proinflammatory senescent cells are present in the brain long-term (months) after TBI and whether ablation of these cells via administration of senolytic drugs can improve long-term functional outcome after TBI. The results revealed that astrocytes and microglia in the cerebral cortex, hippocampus, corpus callosum and lateral posterior thalamus colocalized the senescent cell markers, p16 or p21 at 5 weeks post injury (5wpi) and 4 months post injury (4mpi) in a controlled cortical impact (CCI) model. Intermittent administration of the senolytic drugs, dasatinib and quercetin ( + ) beginning 1-month after TBI for 13 weeks significantly ablated p16-positive- and p21-positive-cells in the brain of TBI animals, and significantly reduced expression of the major senescence-associated secretory phenotype (SASP) pro-inflammatory factors, interleukin-1β and interleukin-6. Senolytic treatment also significantly attenuated neurodegeneration and enhanced neuron number at 18 weeks after TBI in the ipsilateral cortex, hippocampus, and lateral posterior thalamus. Behavioral testing at 18 weeks after TBI further revealed that senolytic therapy significantly rescued defects in spatial reference memory and recognition memory, as well as depression-like behavior in TBI mice.
Taken as a whole, these findings indicate there is robust and widespread induction of senescent cells in the brain long-term after TBI, and that senolytic drug treatment begun 1-month after TBI can efficiently ablate the senescent cells, reduce expression of proinflammatory SASP factors, reduce neurodegeneration, and rescue defects in reference memory, recognition memory, and depressive behavior.
创伤性脑损伤（TBI）后，慢性神经炎症可能持续数月至数年，但其潜在机制仍知之甚少。
在本研究中，我们使用TBI的控制性皮质撞击小鼠模型，以检查促炎性衰老细胞在TBI后长期（数月）是否存在于大脑中，以及通过给予衰老细胞溶解药物消除这些细胞是否能改善TBI后的长期功能结局。结果显示，在控制性皮质撞击（CCI）模型中，损伤后5周（5wpi）和损伤后4个月（4mpi）时，大脑皮质、海马体、胼胝体和丘脑后外侧的星形胶质细胞和小胶质细胞与衰老细胞标志物p16或p21共定位。TBI后1个月开始间歇性给予衰老细胞溶解药物达沙替尼和槲皮素（+），持续13周，可显著消除TBI动物大脑中p16阳性和p21阳性细胞，并显著降低主要衰老相关分泌表型（SASP）促炎因子白细胞介素-1β和白细胞介素-6的表达。衰老细胞溶解治疗还显著减轻了TBI后18周时同侧皮质、海马体和丘脑后外侧的神经退行性变，并增加了神经元数量。TBI后18周的行为测试进一步显示，衰老细胞溶解疗法显著挽救了TBI小鼠的空间参考记忆和识别记忆缺陷以及抑郁样行为。
总体而言，这些发现表明，TBI后长期大脑中会强烈且广泛地诱导衰老细胞，并且TBI后1个月开始的衰老细胞溶解药物治疗可有效消除衰老细胞，降低促炎性SASP因子的表达，减少神经退行性变，并挽救参考记忆、识别记忆和抑郁行为方面的缺陷。
