Modulation of TLR4-mediated inflammatory pathways and oxidative stress by cerium oxide nanoparticles in traumatic brain injury

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-10-03 DOI:10.1016/j.brainresbull.2025.111567

Mohammad Abbas Bejeshk , Mohammad Amin Rajizadeh , Mohammad Khaksari , Mehrdad khatami , Fatemeh Bagheri , Mohadeseh Chahkandi , Ladan Amirkhosravi , Sedigheh Amiresmaili

{"title":"Modulation of TLR4-mediated inflammatory pathways and oxidative stress by cerium oxide nanoparticles in traumatic brain injury","authors":"Mohammad Abbas Bejeshk , Mohammad Amin Rajizadeh , Mohammad Khaksari , Mehrdad khatami , Fatemeh Bagheri , Mohadeseh Chahkandi , Ladan Amirkhosravi , Sedigheh Amiresmaili","doi":"10.1016/j.brainresbull.2025.111567","DOIUrl":null,"url":null,"abstract":"<div><h3>Objects</h3><div>Traumatic brain injury (TBI) induces secondary neurodegeneration by interdependent inflammatory and oxidative processes. While cerium oxide nanoparticles (CeO<sub>2</sub>) exhibit antioxidant potential, regulation of Toll-like receptor 4 (TLR4)-driven neuroinflammation remains to be disclosed. The current study investigates the neuroprotective function of CeO<sub>2</sub> in rat models of diffuse TBI focusing on the modulation of the TLR4 signaling pathway.</div></div><div><h3>Method</h3><div>Thirty-six male Wistar rats (n = 6/group) were randomly assigned to six groups: Sham, DMSO, TBI, and three TBI groups receiving CeO<sub>2</sub> at 0.1, 0.5, or 1 µg/kg. Neuroinflammation (TLR4, TNF-α, IL-1β), markers of oxidative stress (MDA, NO, SOD, GPx), functional recovery through Veterinary Coma Scale (VCS), and histopathological changes were examined.</div></div><div><h3>Results</h3><div>CeO<sub>2</sub> treatment demonstrated significant TLR4 suppression, corresponding with reduced pro-inflammatory cytokine release. The nanoparticles also concurrently inhibited oxidative damage by enhancing endogenous antioxidants. These molecular effects improved neural function, and treated animals were more responsive in motor and alertness tests. Histological analysis showed a reduction in edema in the CeO<sub>2</sub> treated groups compared to the TBI group.</div></div><div><h3>Conclusion</h3><div>The study establishes that CeO<sub>2</sub> exert neuroprotection through following mechanisms: (1) TLR4-mediated anti-inflammatory action and (2) catalytic ROS scavenging. Notably, we identify TLR4 modulation as a previously unrecognized therapeutic target of CeO<sub>2</sub> in TBI. These findings position CeO<sub>2</sub> as a promising multitarget nanotherapeutic for TBI that can treat neuroinflammation and oxidative stress - two principal drivers of secondary injury simultaneously. This research provides groundbreaking evidence for the development of CeO<sub>2</sub> based neuroprotective strategies and offers potential advantages over current pharmacological approaches under clinical evaluation.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"232 ","pages":"Article 111567"},"PeriodicalIF":3.7000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research Bulletin","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S036192302500379X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Objects

Traumatic brain injury (TBI) induces secondary neurodegeneration by interdependent inflammatory and oxidative processes. While cerium oxide nanoparticles (CeO₂) exhibit antioxidant potential, regulation of Toll-like receptor 4 (TLR4)-driven neuroinflammation remains to be disclosed. The current study investigates the neuroprotective function of CeO₂ in rat models of diffuse TBI focusing on the modulation of the TLR4 signaling pathway.

Method

Thirty-six male Wistar rats (n = 6/group) were randomly assigned to six groups: Sham, DMSO, TBI, and three TBI groups receiving CeO₂ at 0.1, 0.5, or 1 µg/kg. Neuroinflammation (TLR4, TNF-α, IL-1β), markers of oxidative stress (MDA, NO, SOD, GPx), functional recovery through Veterinary Coma Scale (VCS), and histopathological changes were examined.

Results

CeO₂ treatment demonstrated significant TLR4 suppression, corresponding with reduced pro-inflammatory cytokine release. The nanoparticles also concurrently inhibited oxidative damage by enhancing endogenous antioxidants. These molecular effects improved neural function, and treated animals were more responsive in motor and alertness tests. Histological analysis showed a reduction in edema in the CeO₂ treated groups compared to the TBI group.

Conclusion

The study establishes that CeO₂ exert neuroprotection through following mechanisms: (1) TLR4-mediated anti-inflammatory action and (2) catalytic ROS scavenging. Notably, we identify TLR4 modulation as a previously unrecognized therapeutic target of CeO₂ in TBI. These findings position CeO₂ as a promising multitarget nanotherapeutic for TBI that can treat neuroinflammation and oxidative stress - two principal drivers of secondary injury simultaneously. This research provides groundbreaking evidence for the development of CeO₂ based neuroprotective strategies and offers potential advantages over current pharmacological approaches under clinical evaluation.

查看原文本刊更多论文

氧化铈纳米颗粒在创伤性脑损伤中对tlr4介导的炎症通路和氧化应激的调节

目的创伤性脑损伤（TBI）通过相互依赖的炎症和氧化过程诱导继发性神经退行性变。虽然氧化铈纳米颗粒（CeO2）具有抗氧化潜力，但toll样受体4 （TLR4）驱动的神经炎症的调控仍有待揭示。本研究主要探讨CeO2在弥漫性脑损伤大鼠模型中的神经保护作用，重点研究其对TLR4信号通路的调节作用。方法36只雄性Wistar大鼠（n = 6只/组）随机分为Sham、DMSO、TBI组和TBI组，分别给予0.1、0.5、1 µg/kg浓度的CeO2。观察神经炎症（TLR4、TNF-α、IL-1β）、氧化应激标志物（MDA、NO、SOD、GPx）、动物昏迷量表（VCS）功能恢复情况及组织病理学变化。结果sceo2治疗可显著抑制TLR4，降低促炎细胞因子的释放。纳米颗粒还通过增强内源性抗氧化剂同时抑制氧化损伤。这些分子效应改善了神经功能，治疗后的动物在运动和警觉性测试中反应更灵敏。组织学分析显示，与TBI组相比，CeO2治疗组水肿减少。结论CeO2通过以下机制发挥神经保护作用：(1)tlr4介导的抗炎作用和(2)催化活性氧清除作用。值得注意的是，我们发现TLR4调节是以前未被认识到的CeO2在TBI中的治疗靶点。这些发现表明，CeO2是一种很有前途的多靶点纳米治疗TBI的药物，可以同时治疗神经炎症和氧化应激——这两个主要的继发性损伤驱动因素。本研究为开发基于CeO2的神经保护策略提供了突破性的证据，并在临床评估中提供了比当前药理学方法潜在的优势。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.