Neurotherapeutics
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2024
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IF 5.6
Zhiyuan Shen,Yuxuan Lu,Yingying Ren,Zhaoxia Wang,Jianwen Deng,Ding Nan,Jingjing Jia,Weiwei Yu,Yunyi Jin,Wei Sun,Yining Huang,Xiaozhong Qu,Haiqiang Jin
The precise oxygen content thresholds of ischemic deep parenchymal (OCIDP) and that in cortical microcirculation (OCCM), which leads to ischemic penumbra converting into the infarcted core, remain uncertain. This study employed an invasive fiber-optic oxygen meter and a newly developed oxygen-responsive probe called RuA 3 -Cy5-rtPA (RC-rtPA) based on recombinant tissue-type plasminogen activator (rtPA) to examine the oxygen content thresholds. A mouse model of middle cerebral artery occlusion was generated and animals were randomly divided into a sham, 24-h reperfusion after 3-h ischemia (IR 3-h), and IR 6-h groups, all of which were sacrificed following reperfusion. Stroke severity was evaluated based on the infarction area, neurological symptoms, microcirculation perfusion, and microemboli in microcirculation. OCIDP was characterized based on its extent and distribution, whereas OCCM was measured using RC-rtPA. During ischemia, stroke severity escalation manifested as increasing infarction area, severe neurologic symptoms, and poorer microcirculation perfusion with more microthrombi depositions. OCIDP presented rapid decline following artery occlusion along with a gradual increase in the hypoxic area. Within 3 h following ischemia induction, the ischemic tissue that experienced hypoxia could be rescued, and this reversibility would disappear after 6 h. Within 6 h, OCCM continued to decrease. A significant decrease in oxygen content in cortical venules and cortical parenchyma was observed. These findings assist in establishing the extent of the ischemic penumbra at the microcirculation level and offer a foundation for assessing the ischemic penumbra that could respond positively to reperfusion therapy beyond the typical time window.
研究领域:
神经科学
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中风
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微循环
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氧测量
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动物模型
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2020
·Vol. 45
·期 5
·1107-1119
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IF 3.038
Xiao Zhang Hong,Wang Li,Gan Ping,He Jing,Yan Bing Chun,Ding Li Dong
miR-126 which is considered one of the most important miRNAs for maintaining vascular integrity, plays an important role in neuroprotection after cerebral ischemia–reperfusion (I-R). Moreover, vascular endothelial growth factor A (VEGFA), sprouty-related EVH1 domain-containing protein 1 (SPRED1), and Raf-1 are also involved in physiological processes of vascular endothelial cells (ECs). This study investigated how miR-126 changes with reperfusion time in different brain tissues after global cerebral ischemia and focal cerebral ischemia and examined the underlying mechanism miR-126 involving VEGFA, SPRED1, and Raf-1 after I-R. The results indicated decreases in the levels of miR-126-3p and miR-126-5p expression in mice and gerbils after I-R, consistent with the results after oxygen and glucose deprivation and reperfusion (OGD/R) in PC12 cells. Glial cells were activated as neuronal damage gradually increased after I-R. Inhibition of miR-126-3p exacerbated the OGD/R-induced cell death and reduced cell viability. After miR-126-3p inhibition, the levels of SPRED1 and VEGFA expression were increased, and p -Raf-1 expression was decreased after OGD/R. Moreover, based on the intervention of miR-126-3p inhibition, we found that the expression of p -Raf-1 was significantly increased after the intervention of siSPRED1 , while it was not statistically significant after intervention of siVEGFA . The reduction of miR-126 expression after global and focal cerebral ischemia exacerbated neuronal death, which was closely related to increasing the SPRED1 activation and inhibiting the Raf-1 expression.
研究领域:
神经科学
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分子生物学
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脑血管疾病
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Shanshan Liu,Jianpei Xu,Yipu Liu,Yang You,Laozhi Xie,Shiqiang Tong,Yu Chen,Kaifan Liang,Songlei Zhou,Fengan Li,Zhuang Tang,Ni Mei,Huiping Lu,Xiaolin Wang,Xiaoling Gao,Jun Chen
High level of detrimental factors including reactive oxygen species (ROS) and inflammatory cytokines accumulated in the infarct core and their erosion to salvageable penumbra are key pathological cascades of ischemia-reperfusion injury in stroke. Few neuroprotectants can remodel the hostile microenvironment of the infarct core for the failure to interfere with dead or biofunctionally inactive dying cells. Even ischemia-reperfusion injury is temporarily attenuated in the penumbra by medications; insults of detrimental factors from the core still erode the penumbra continuously along with drug metabolism and clearance. Herein, a strategy named “nanobuffer” is proposed to neutralize detrimental factors and buffer destructive erosion to the penumbra. Inspired by neutrophils’ tropism to the infarct core and affinity to inflammatory cytokines, poly(lactic-co-glycolic acid) (PLGA) nanoparticles are coated with neutrophil membrane to target the infarct core and absorb inflammatory cytokines; α-lipoic acid is decorated on the surface and cannabidiol is loaded for ROS scavenging and neuroprotection, respectively, to construct the basic unit of the nanobuffer. Such a nanobuffer exerts a comprehensive effect on the infarct area via detrimental factor neutralization and cannabidiol-induced neuroprotection. Besides, the nanobuffer can possibly be enhanced by dynamic ROP (ring-opening-polymerization)-induced membrane cross-fusion among closely adjacent units in vivo. Systematic evaluations show significant decrease of detrimental factors in the core and the penumbra, reduced infarct volume, and improved neurological recovery compared to the untreated group of stroke rats.
研究领域:
神经科学
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药学
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生物医学工程
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DOI
PubMed
高影响因子
The Innovation
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2024
·
IF 33.2
Mengjie Jia,Wenjun Miao,Yiliang Li,Yajie Guo,Jieying Zeng,Yan Gao,Xinting Li,Yufan Wang,Zhenghuan Zhao,Zichen Xu,Nancy Wang,Fang Yang,Jing Zhao,Yi Wang,Guixue Wang
This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation, in which neutrophil extracellular vesicles (NEVs) are coated onto reactive oxygen species (ROS)-sensitive probucol-based polyprodrug nanoparticles (NPPBNPs). This NEV-camouflaged biomimetic nanoformulation holds significant potential for the effective treatment of cerebral ischemia-reperfusion injury (CIRI), offering multifaceted therapeutic effects, such as ROS elimination, inhibition of oxidative stress-induced neuronal apoptosis, attenuation of glial hyperactivation, and suppression of pro-inflammatory mediator secretion. In a murine CIRI model, NPPBNPs markedly enhanced neuronal viability, ameliorated the ischemic penumbra, restored behavioral functions, and exhibited an acceptable safety profile. The therapeutic mechanism of NPPBNPs involves NEV-mediated camouflage, which enables selective targeting of the pathological endothelium, thereby reducing peripheral neutrophil recruitment and facilitating blood-brain barrier (BBB) transport. Upon internalization by neurons, astrocytes, and microglia within ischemic regions, NPPBNPs respond to elevated intracellular ROS levels by releasing probucol in a controlled manner, which synergistically mitigates oxidative stress and inflammatory responses in CIRI-affected areas. Collectively, this multifunctional biomimetic nanoformulation represents a promising and practical strategy for the safe and effective treatment of CIRI.
研究领域:
药学
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神经科学
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纳米技术
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生物医学工程
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产品关联
DOI
高影响因子
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