Organophosphate pesticide trichlorfon induced neurotoxic effects in freshwater silver catfish Rhamdia quelen via disruption of blood-brain barrier: Implications on oxidative status, cell viability and brain neurotransmitters

Abstract Ischemic stroke (IS) is a major neurological disease with high fatality and residual disability burdens. Increasing amount of long noncoding RNAs (lncRNAs) have been revealed to play an important role in ischemic stroke. However, the roles and significances of most lncRNAs in ischemic stroke are still unknown.This study was performed to identify differentially expressed lncRNAs using a lncRNA microarray in whole blood samples of patients suffered from acute cerebral ischemia. Bioinformatics analyses including GO, KEGG pathway enrichment analysis, and proximity to putative stroke risk location analysis were performed. A novel lncRNA ENST00000530525 significantly decreased after ischemic stroke. Furthermore, we evaluated lncRNA ENST00000530525 expression in cultured hCMEC/D3 cells under oxygen-glucose deprivation/reoxygenation(OGD/R) conditions using fluorescent in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (RT-qPCR) analysis. To investigate the function of lncRNA ENST00000530525, the plasmid of overexpression(OE) and negative control(NC) were transfected into hCMEC/D3, then cell viability was detected by cell counting kit-8 (CCK-8) Assay after OGD/R,lncRNA ENST00000530525 and ANO1 expression were investigated using RT-qPCR and Immunofluorescence. For blood-brain barrier(BBB) permeability,FITC-dextran transendothelial permeability assay and Tight junction(Tj) protein was detected.There were 3352 differentially expressed lncRNAs in blood samples of acute ischemic stroke patients. The validation results were consistent with gene chip data.GO and KEGG results showed these lncRNAs were mainly related to oxygen and glucose metabolism, leukocyte transendothelial migration,mitophagy and cellular senescence.Among these, lncRNA ENST00000530525 was the highly down-regulated lncRNA and mapped within the ischemic stroke associated gene anoctamin-1 (ANO1). We furtherly found lncRNA ENST00000530525 was down-regulated in hCMEC/D3 cells under 4h OGD and 20h reoxygenation(OGD4/R20) conditions. Up-regulating lncRNA ENST00000530525 decreased the cell viability while increased ANO1 expression and contributed to BBB injury of hCMEC/D3 cells after OGD4/R20.The lncRNA ENST00000530525 might plays deleterious roles in post-stroke pathogenesis. The results show light on some differentially expressed lncRNAs in human certainly participate through characteristic roles in post-stroke pathogenesis, thus, the roles and significances of some novel lncRNAs in ischemic stroke thereby warranting further study.

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Influence of T-2 and HT-2 Toxin on the Blood-Brain Barrier In Vitro: New Experimental Hints for Neurotoxic Effects

PLoS ONE ◽

10.1371/journal.pone.0060484 ◽

2013 ◽

Vol 8 (3) ◽

pp. e60484 ◽

Cited By ~ 49

Author(s):

Maria Weidner ◽

Sabine Hüwel ◽

Franziska Ebert ◽

Tanja Schwerdtle ◽

Hans-Joachim Galla ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Blood Brain ◽

Neurotoxic Effects

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Methamphetamine Disrupts Blood–Brain Barrier Function by Induction of Oxidative Stress in Brain Endothelial Cells

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.112 ◽

2009 ◽

Vol 29 (12) ◽

pp. 1933-1945 ◽

Cited By ~ 124

Author(s):

Servio H Ramirez ◽

Raghava Potula ◽

Shongshan Fan ◽

Tess Eidem ◽

Anil Papugani ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Blood Brain Barrier ◽

Endothelial Injury ◽

Brain Barrier ◽

Dependent Manner ◽

Monocyte Migration ◽

Enhanced Production ◽

Blood Brain ◽

Neurotoxic Effects

Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood–brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.

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Abstract T P250: Role of Autophagy in Blood-Brain Barrier Disruption and Tight Junction Degradation Under Ischemic Condition

Stroke ◽

10.1161/str.46.suppl_1.tp250 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Kyeong-A Kim ◽

Young-Jun Shin ◽

Eun-Sun Kim ◽

Muhammad Akram ◽

Dabi Noh ◽

...

Keyword(s):

Ischemic Stroke ◽

Tight Junction ◽

Cell Viability ◽

Blood Brain Barrier ◽

Neuronal Damage ◽

Cell Damage ◽

Brain Barrier ◽

Blood Brain ◽

Junction Protein

During ischemic stroke, the integrity of blood-brain barrier (BBB), which shows selective permeability for substances to brain, is significantly damaged amplifying ischemic neuronal damage. There have been attempts to identify the exact mechanism ischemic BBB disruption to minimize brain damage under ischemic stroke. Autophagy is catabolic process which involves degradation and recycling of damaged or unnecessary organelles. However, excessive autophagy can induce cell damage and death under pathological conditions such as ischemia. In this study, we evaluated if autophagy is a key mechanism of BBB dysfunction under ischemic stroke. In vitro BBB model of bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), an ischemic mimic condition. After exposure to OGD for 18 hours, cell viability was significantly decreased and cellular permeability was impaired. The conversion of LC3-I to LC3-II and puncta of LC3 in bEnd.3 were increased, demonstrating that autophagy is induced under ischemic condition. Modulation of autophagy by 3-methyladenine, an autophagy inhibitor, reversed the conversion of LC3 as well as decreased cell viability, suggesting that autophagy involves in ischemic BBB damage. The level of occludin, a tight junction protein in BBB, was decreased after OGD, and this was reversed by inhibition of autophagy. Our findings showed that induction of autophagy might contribute to increased permeability through occludin degradation in brain endothelial cells under ischemia, providing a new mechanism of BBB disruption in ischemic stroke.

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