实验性缺血性中风期间,钙蛋白酶通过上调 PARP-NF-κB 信号参与神经血管单元损伤。

IF 4.6 2区 医学 Q1 NEUROSCIENCES Molecular Neurobiology Pub Date : 2024-10-01 Epub Date: 2024-03-12 DOI:10.1007/s12035-024-04092-w
Wenhao Yan, Chunyang Wang, Yumei Zhao, Yingying Jiang, Ming Sun
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引用次数: 0

摘要

据报道,钙蛋白酶和 PARP-NF-κB 信号转导参与了缺血性脑损伤。本研究探讨了在实验性缺血性脑卒中中,钙蛋白酶是否通过上调 PARP-NF-κB 信号而导致神经血管单元(NVU)损伤。雄性 Sprague-Dawley 大鼠在大脑中动脉闭塞 90 分钟后接受再灌注。通过血脑屏障(BBB)的通透性、细胞外基质和紧密连接中蛋白质的降解以及超微结构的变化来评估NVU的损伤。炎症反应是通过 PARP-NF-κB 信号转导驱动的炎症基因的表达和髓过氧化物酶(MPO)的活性来确定的。钙蛋白酶抑制剂 MDL 28,170 可改善缺血大鼠的神经功能、降低 TUNEL 染色指数、减轻脑肿胀并缩小梗死体积。此外,它还能降低 BBB 的通透性,提高层粘连蛋白、胶原蛋白 IV 和闭塞素的水平,减轻缺血诱导后半影和核心区 NVU 的超微结构损伤。同时,它还能提高细胞膜 IκBα 的水平,降低核 PARP 和 NF-κB p65 的水平,降低半影和核心区 ICAM-1、TNF-α、IL-1β、MMP-9 和 MMP-2 的水平,抑制 MPO 的活性。这些数据表明,抑制钙蛋白酶可抑制PARP-NF-κB信号介导的炎症反应,减轻NVU损伤,保护大脑免受缺血性脑卒中的损害,提示钙蛋白酶在脑缺血时通过上调PARP-NF-κB信号参与了NVU损伤。
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Involvement of Calpain in Neurovascular Unit Damage through Up-regulating PARP-NF-κB Signaling during Experimental Ischemic Stroke.

Calpain and PARP-NF-κB signaling are reported to participate in the ischemic brain injury. In this study, it was investigated whether calpain was contributed to the neurovascular unit (NVU) damage through up-regulating PARP-NF-κB signaling during experimental ischemic stroke. Male Sprague-Dawley rats were suffered from 90 min of middle cerebral artery occlusion, followed by reperfusion. The NVU damage was evaluated by the permeability of blood-brain barrier (BBB), the degradation of proteins in extracellular matrix and tight junctions, and ultrastructural changes. The inflammatory response was determined by the expression of inflammatory genes driven by PARP-NF-κB signaling and the activities of myeloperoxidase (MPO). Treatment with MDL 28,170, a calpain inhibitor, improved neurological functions, reduced TUNEL staining index, lessened brain swelling, and decreased infarct volume in ischemic rats. Moreover, it reduced the BBB permeability, enhanced the levels of laminin, collagen IV and occludin, and attenuated the ultrastructural damage of NVU in penumbra and core after induction of ischemia. Meanwhile, it enhanced the levels of cytosolic IκBα, lessened the levels of nuclear PARP and NF-κB p65, reduced the levels of ICAM-1, TNF-α, IL-1β, MMP-9, and MMP-2,and suppressed the activities of MPO in penumbra and core. These data showed that calpain inhibition suppressed PARP-NF-κB signaling-mediated inflammatory response, reduced NVU damage, and protected brain against ischemic stroke, suggesting the involvement of calpain in the NVU damage through up-regulating PARP-NF-κB signaling during brain ischemia.

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来源期刊
Molecular Neurobiology
Molecular Neurobiology 医学-神经科学
CiteScore
9.00
自引率
2.00%
发文量
480
审稿时长
1 months
期刊介绍: Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.
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