Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice.
Senolytic therapy is neuroprotective and improves functional outcome long-term after traumatic brain injury in mice.
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衰老清除疗法具有神经保护作用，可改善小鼠创伤性脑损伤后的长期功能结局。
DOI：
10.3389/fnins.2023.1227705
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发表时间：
2023
影响因子：
4.3
通讯作者：
Brann, Darrell W.
中科院分区：
文献类型：
--
作者：
Wang, Jing;Lu, Yujiao;Carr, Christopher;Dhandapani, Krishnan M.;Brann, Darrell W.
创伤性脑损伤(TBI)后可存在数月至数年的慢性神经炎，尽管其潜在的机制仍不清楚。在目前的研究中，我们使用了一种受控的皮质撞击脑损伤小鼠模型来检查脑损伤后长期(几个月)脑内是否存在促炎衰老细胞，以及通过应用促衰老药物来消融这些细胞是否可以改善脑损伤后的长期功能结果。结果表明，在皮质撞击伤后5 周(5wpi)和4 个月(4mpi)，大脑皮质、海马体、胼胝体和丘脑外侧后部的星形胶质细胞和小胶质细胞共定位衰老细胞标志物p16INK4a或p21Cip1/Waf1。从脑损伤后1个月开始间断应用抗衰老药物达沙替尼和槲皮素(D + Q)，持续13 周，可显著消融脑损伤动物脑内p16INK4a和p21Cip1/Waf1阳性细胞，并显著降低主要衰老相关分泌表型促炎因子IL-1β和IL-6的表达。在脑损伤后18 周，神经溶解治疗也显著减轻了同侧皮质、海马区和丘脑外侧后部神经元的变性和神经元数量的增加。在脑损伤后18 周的行为测试进一步显示，感觉溶解疗法显著挽救了脑损伤小鼠空间参考记忆和再认记忆的缺陷，以及抑郁样行为。综上所述，这些发现表明，脑损伤后长期存在着强有力且广泛的衰老细胞诱导，脑损伤后1个月开始的抗衰老药物治疗可以有效地去除衰老细胞，减少促炎性SASP因子的表达，减少神经变性，并挽救参考记忆、再认记忆和抑郁行为的缺陷。
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, p16Ink4a or p21Cip1/Waf1 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 (D + Q) beginning 1-month after TBI for 13 weeks significantly ablated p16Ink4a-positive- and p21Cip1/Waf1-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.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
4.7
作者：
Laird MD;Sukumari-Ramesh S;Swift AE;Meiler SE;Vender JR;Dhandapani KM
通讯作者：
Dhandapani KM
影响因子：
3.9
作者：
Chinta, Shankar J.;Woods, Georgia;Andersen, Julie K.
通讯作者：
Andersen, Julie K.
影响因子：
11.1
作者：
Hickson, LaTonya J.;Prata, Larissa G. P. Langhi;Kirkland, James L.
通讯作者：
Kirkland, James L.
DOI：
10.1038/nrd.2017.116
发表时间：
2017-10
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Childs BG;Gluscevic M;Baker DJ;Laberge RM;Marquess D;Dananberg J;van Deursen JM
通讯作者：
van Deursen JM