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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2022, Vol. 42 Issue (12): 1-11    DOI: 10.13523/j.cb.2207022
    
Protective Effects of Copper Nanoparticles Against the Neurovascular Unit after Ischemic Stroke
HUANG Ji-an,LI Wan-meng,LIU Wei,QI Zi-tong,ZHAO Liang()
School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China
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Abstract  

Objective: To study the protective effect of copper nanoparticles (Cu-nps) on the neurovascular units(NVU) after ischemic stroke. Methods: Cu-nps was synthesized by heating and stirring method. A model of rat transient middle cerebral artery occlusion/ reperfusion (tMCAO) was established in vivo. The experiment was divided into three groups, including normal group (Sham), model group (tMCAO), and dosing group (Cu-nps). Brain infarction area, neural apoptosis, blood-brain barrier (BBB) integrity, and related protein expression were detected in each group. Results: Cu-nps were successfully prepared and present in the form of Cu2+ with a uniform particle size around 80 nm and good biocompatibility. Cu-nps target damaged neurons in cerebral ischemia, improve neuronal cell viability, reduce reactive oxygen species (ROS), reduce neuronal apoptosis and cerebral infarct area, and reduce EB dye leakage and inflammatory cytokine expression. Conclusion: Cu-nps reduce cerebral ischemia-reperfusion injury, protect BBB integrity, reduce oxidative stress, protect NVU function and therefore reduce glial cell activation.

Key words： Copper nanoparticles      Ischemic stroke      Neurovascular unit      Ischemia-reperfusion injury     
Received: 13 July 2022      Published: 05 January 2023
ZTFLH:  R94  
Corresponding Authors: Liang ZHAO     E-mail: liangzhao79@163.com
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Ji-an HUANG
Wan-meng LI
Wei LIU
Zi-tong QI
Liang ZHAO
Cite this article:

HUANG Ji-an,LI Wan-meng,LIU Wei,QI Zi-tong,ZHAO Liang. Protective Effects of Copper Nanoparticles Against the Neurovascular Unit after Ischemic Stroke. China Biotechnology, 2022, 42(12): 1-11.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2207022     OR     https://manu60.magtech.com.cn/biotech/Y2022/V42/I12/1

Fig.1 Morphology and structure characterization of Cu-nps (a) SEM image of Cu-nps (b) TEM image of Cu-nps (c) Particle size distribution of Cu-nps (d) The XPS spectrum for the elements Cu in Cu-nps (e) The XPS spectrum for the elements C in Cu-nps (f) The XPS spectrum for the elements N in Cu-nps (g) The XPS spectrum for the elements O in Cu-nps (h) The XPS spectrum for the elements Cu, C, N and O in Cu-nps (i) The XRD of Cu-nps (j) Representative fluorescent images of PKH26 labelled Cu-nps in brains from tMCAO rats receiving 40 min and 2 h of intravenous administration of PKH26 labelled Cu-nps (k) Co-location of PKH26 labelled Cu-nps (red) with SH-SY5Y cells (blue) after 1 h and 3 h
Fig.2 Cu-nps reversed the OGD induced damage of neurons in tMCAO rats (a) The cell viability of OGD cells treated with Cu-nps (b) ROS of OGD cells treated with Cu-nps (c) Images of apoptotic cells in OGD cells treated with Cu-nps in tunel assay (d) Representative immunofluorescence staining for neuron positive cells, DAPI (blue) was used as a nuclear marker (e) Representative brain slices with infarcts stained by TTC from each group in tMCAO rats (f) Infarct percentages in the tMCAO/R model treated with Cu-nps (g) Zea-Longa neurological scores (h) Ludmila belayev neurological scores. Data represent means ± SD (n = 3), * P<0.05, ** P<0.01, *** P<0.001
Fig.3 Cu-nps protected against BBB breakdown by promoting elevating tight junction proteins (a) Representative images of EB extravasation in different groups after 2 h ischemia/24 h reperfusion and amount of leaking EB in brain of different groups was quantified (b) Western analysis on the expression levels of MMP2, MMP9, Occludin and Claudin 5 proteins in microvessel extracts from ischemic brain (c) Western analysis on the expression levels of GFAP, CD206, iNOS, IL-6, 1L-1βand IL-10 proteins in microvessel extracts from ischemic brain. Data represent means ± SD (n=3), ** P<0.01, *** P<0.001
Fig.4 Biocompatibility evaluation of Cu-nps (a) The viability of SH-SY5Y cells at 24 h after treatment with different concentrations of Cu-nps (b) Haemolysis determined by observing whether the red blood cells were ruptured after treatment with different concentrations of Cu-nps
Number 1 2 3 4 5 6
2% Red blood cell solution /mL 2.5 2.5 2.5 2.5 2.5 2.5
Normal saline /mL - 2.5 0.5 1.5 2 2.25
Distilled water /mL 2.5 - - - - -
Cu-nps /mL - - 2 1 0.5 0.25
Table 1 The ratio of Cu-nps material, mass fraction is 2% red blood cell suspension, and physiological saline
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