Role of the neurovascular unit in the process of cerebral ischemic injury

Zhao, Yu; Yang, Jiehong; Li, Chang; Zhou, Guoying; Wan, Haofang; Ding, Zhongxiang; Zhou, Huifen

doi:10.1016/j.phrs.2020.105103

Cited by 27 publications

(20 citation statements)

References 266 publications

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“…In cerebral ischemic diseases, such as ischemic stroke, ischemic/reperfusion (I/R) injury is inevitable after treatment like thrombolytic therapy [1][2][3]. However, the treatment of cerebral I/R injury as well as its molecular mechanisms remain as a problem.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine inhibits inflammatory response and oxidative stress through regulating miR-205-5p by targeting HMGB1 in cerebral ischemic/reperfusion

Yang

Zhao

Yin

et al. 2021

Immunopharmacology and Immunotoxicology

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Objective: To investigate effects of dexmedetomidine (DEX) on miR-205-5p/HMGB1 axis in cerebral ischemic/reperfusion (I/R) injury. Methods: Both in vivo I/R rat model and in vitro hypoxia/reoxygenation (H/R) cell model using rat hippocampal neurons cells were established. miR-205-5p was overexpressed or inhibited by transfection of miR-205-5p mimics or inhibitor. HMGB1 was overexpressed by transfection overexpression plasmids (OE-HMGB1). TTC staining was used for measurement of infraction volume. Oxidative stress was evaluated by measurement of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) and inflammation was evaluated by measurement of IL-1b, IL-6 and TNF-a. Dual luciferase reporter assay was performed to confirm binding between miR-205-5p and HMGB1. The expression levels of miR-205-5p, and HMGB1 were measured using RT-qPCR. Western blotting was used to test the protein expression levels of HMGB1, nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase (GPx), glutathione reductase (GR), heme oxygenase 1 (HO-1) and catalase (CAT). Results: Treatment of DEX significantly reduced brain infraction volume, decreased Longa's neurological function score and inhibited oxidative stress and inflammation in brain tissues of I/R rats, which were all reversed by inhibition of miR-205-5p. Both treatment of DEX or overexpression of miR-205-5p restricted oxidative stress and inflammation in H/R rat hippocampal neurons cells. The inhibition of miR-205-5p reversed the effects of DEX, while the overexpression of HMGB1 reversed the effects of miR-205-5p overexpression in H/R rat hippocampal neurons cells. Dual luciferase reporter assay showed miR-205-5p directly targeted HMGB1. Conclusion: DEX improved I/R injury by suppressing brain oxidative stress and inflammation DEX improved I/R injury by suppressing brain oxidative stress and inflammation through activating miR-205-5p/HMGB1 axis through activating miR-205-5p/HMGB1 axis.

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Section: Introductionmentioning

confidence: 99%

Dexmedetomidine inhibits inflammatory response and oxidative stress through regulating miR-205-5p by targeting HMGB1 in cerebral ischemic/reperfusion

Yang

Zhao

Yin

et al. 2021

Immunopharmacology and Immunotoxicology

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“…Astrocytes, neurons and vascular endothelial cells are the main components of the NVU ( 15 ). Therefore, the effects of NBP combined with edaravone on the NVU were evaluated using the cell immunoreactivity of astrocytes, neurons and vascular endothelial cells, visualized using immunofluorescence staining.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, the neurovascular unit (NVU) has attracted the attention of researchers as it emphasizes the importance of communication among neurons, endothelial cells and astrocytes, instead of only blood vessels or neurons, in ischemic injuries ( 15 ). The NVU contributes to disease development and responses; therefore, it could be a therapeutic target ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Protective multi‑target effects of DL‑3‑n‑butylphthalide combined with 3‑methyl‑1‑phenyl‑2‑pyrazolin‑5‑one in mice with ischemic stroke

Guan

Liu

et al. 2021

Mol Med Rep

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DL-3-n-butylphthalide (NBP) and 3-methyl-1- phenyl-2-pyrazolin-5-one (edaravone) are acknowledged neuroprotective agents that protect against ischemic stroke. However, the underlying mechanisms of a combination therapy with NBP and edaravone have not yet been fully clarified. The aim of the present study was to explore whether the co-administration of NBP and edaravone had multi-target protective effects on the neurovascular unit (NVU) of mice affected by ischemic stroke. Male C57BL/6 mice were randomly divided into the following three groups: i) Sham operation control, ii) middle cerebral artery occlusion (MCAO) and reperfusion, iii) and MCAO/reperfusion with the co-administration of NBP (40 mg/kg) and edaravone (6 mg/kg) delivered via intraperitoneal injection at 0 and 4 h after reperfusion (NBP + edaravone). After ischemia and reperfusion, infarct volumes and neurological deficits were evaluated. The immunoreactivity of the NVU, comprising neurons, endothelial cells and astrocytes, was determined using immunofluorescence staining of neuronal nuclei (NeuN), platelet and endothelial cell adhesion molecule 1 (CD31) and glial fibrillary acidic protein (GFAP). Western blotting was used to detect the expression levels of apoptosis-related proteins. The infarct volume, neurological function scores and cell damage were increased in the MCAO group compared with the sham operation group. Furthermore, the MCAO mice had reduced NeuN and CD31 expression and increased GFAP expression compared with the sham group. By contrast, the NBP + edaravone group exhibited reduced cell damage and consequently lower infarct volume and neurological deficit scores compared with the MCAO group. The NBP + edaravone group exhibited increased NeuN and CD31 expression and decreased GFAP expression compared with the MCAO group. Furthermore, the expression levels of Bax and cleaved caspase-3 in the NBP + edaravone group were decreased significantly compared with the MCAO group, while the expression levels of Bcl-2 and mitochondrial cytochrome c were increased. In conclusion, the results of the present study demonstrated that NBP and edaravone effectively prevented ischemic stroke damage with multi-target protective effects. In addition, NBP + edaravone may be a promising combination therapy for ischemic stroke.

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“…First, the NVU is a complex structural and functional unit. It consists of BMEC, neurons, astrocytes, microglial cells, and the extracellular matrix 46 . In this study, the NVU system was established using a triple cell co‐culture model (neurons, astrocytes, and BMEC), and the role of microglial cells and extracellular matrix has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

The AMPAR antagonist perampanel protects the neurovascular unit against traumatic injury via regulating Sirt3

et al. 2021

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Introduction Perampanel is a highly selective and noncompetitive α‐amino‐3 ‐hydroxy‐5‐methyl‐4‐isoxazole propionate receptor (AMPAR) antagonist, which has been used as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was shown to exert neuroprotective effects in hemorrhagic and ischemic stroke models via regulating blood–brain barrier (BBB) function. Aim Here, the protective effects of perampanel were investigated in an in vitro neurovascular unit (NVU) system established using a triple cell co‐culture model (neurons, astrocytes, and brain microvascular endothelial cells) and in an in vivo traumatic brain injury (TBI) model. Results Neurons in the NVU system exhibit a more mature morphological phenotype compared with neurons cultured alone, and the co‐culture system mimicked an impermeable barrier in vitro. Perampanel protects the NVU system against traumatic and excitotoxic injury, as evidenced by reduced lactate dehydrogenase (LDH) release and apoptotic rate. Treatment with perampanel attenuated lipid peroxidation and expression of inflammatory cytokines. In addition, perampanel increased Sirt3 protein expression, enhanced the activities of mitochondrial enzyme IDH2 and SOD2, and preserved BBB function in vitro. Knockdown of Sirt3 using specific siRNA (Si‐Sirt3) partially reserved the effects of perampanel on neuronal injury and BBB function. Treatment with perampanel in vivo attenuated brain edema, preserved neurological function, inhibited apoptosis and microglia activation after TBI. Furthermore, perampanel increased the expression of Sirt3 and preserved BBB function after TBI. The effect of perampanel on BBB function and brain edema was abolished by knockdown of Sirt3 in vivo. Conclusion Our results indicate that the noncompetitive AMPAR antagonist perampanel protects the NVU system and reduces brain damage after TBI via activating the Sirt3 cascades.

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Role of the neurovascular unit in the process of cerebral ischemic injury

Cited by 27 publications

References 266 publications

Dexmedetomidine inhibits inflammatory response and oxidative stress through regulating miR-205-5p by targeting HMGB1 in cerebral ischemic/reperfusion

Dexmedetomidine inhibits inflammatory response and oxidative stress through regulating miR-205-5p by targeting HMGB1 in cerebral ischemic/reperfusion

Protective multi‑target effects of DL‑3‑n‑butylphthalide combined with 3‑methyl‑1‑phenyl‑2‑pyrazolin‑5‑one in mice with ischemic stroke

The AMPAR antagonist perampanel protects the neurovascular unit against traumatic injury via regulating Sirt3

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