Antioxidant theranostic copolymer-mediated reduction in oxidative stress following traumatic brain injury improves outcome in a mouse model.
Antioxidant theranostic copolymer-mediated reduction in oxidative stress following traumatic brain injury improves outcome in a mouse model.
复制标题
抗氧化治疗诊断共聚物介导的创伤性脑损伤后氧化应激的减少可改善小鼠模型的结果。
DOI：
10.1002/adtp.202300147
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发表时间：
2023
影响因子：
4.6
通讯作者：
Kievit,ForrestM
中科院分区：
文献类型：
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作者：
Tarudji,AriaW;Gee,ConnorC;Miller,HunterA;Steffen,Rylie;Curtis,EvanT;Priester,AaronM;Convertine,AnthonyJ;Kievit,ForrestM
创伤性脑损伤（TBI）后，产生过量的活性氧（ROS）和脂质过氧化产物（LPOx），导致原发性损伤以外的继发性损伤。目前治疗的一个主要限制是靶点参与度差，这阻碍了临床试验的成功。因此，基于纳米颗粒的治疗最近受到关注，因为它们能够增加受损大脑中的积累和保留。含有硫醇官能团的治疗诊断神经保护共聚物（NPC 3）可以中和ROS和LPOx。在受控皮质撞击（CCI）小鼠模型中，损伤后立即给予NPC 3提供了降低ROS水平的治疗窗口，雄性为2.08-20.83 mg kg− 1，雌性为5.52-27.62 mg kg− 1。NPC 3介导的氧化应激减少改善了男性的空间学习和记忆，而女性的改善幅度很小。值得注意的是，NPC 3介导的氧化应激减少可防止雄性小鼠坏死的双侧扩散，这在雌性小鼠中未观察到，可能是基于性别的空间学习和记忆差异的原因。总的来说，这些发现表明氧化应激清除剂纳米颗粒治疗的性别差异，以及在受损大脑中提供治疗益处的抗氧化活性的可能上限，因为雌性小鼠从NPC 3治疗中获益的程度低于雄性小鼠。
Following a traumatic brain injury (TBI), excess reactive oxygen species (ROS) and lipid peroxidation products (LPOx) are generated and lead to secondary injury beyond the primary insult. A major limitation of current treatments is poor target engagement, which has prevented success in clinical trials. Thus, nanoparticle‐based treatments have received recent attention because of their ability to increase accumulation and retention in damaged brain. Theranostic neuroprotective copolymers (NPC3) containing thiol functional groups can neutralize ROS and LPOx. Immediate administration of NPC3 following injury in a controlled cortical impact (CCI) mouse model provides a therapeutic window in reducing ROS levels at 2.08–20.83 mg kg−1in males and 5.52–27.62 mg kg−1in females. This NPC3‐mediated reduction in oxidative stress improves spatial learning and memory in males, while females show minimal improvement. Notably, NPC3‐mediated reduction in oxidative stress prevents the bilateral spread of necrosis in male mice, which is not observed in female mice and likely accounts for the sex‐based spatial learning and memory differences. Overall, these findings suggest sex‐based differences to oxidative stress scavenger nanoparticle treatments, and a possible upper threshold of antioxidant activity that provides therapeutic benefit in injured brain since female mice benefit from NPC3 treatment to a lesser extent than male mice.