N-methyl-D-aspartic acid increases tight junction protein destruction in brain endothelial cell via caveolin-1-associated ERK1/2 signaling

Mao, Fengping; Huang, Feizhou; Nong, Weidong; Lao, Dayuan; Gong, Zhuowei; Huang, Wen Cheng

doi:10.1016/j.tox.2022.153139

Cited by 9 publications

(9 citation statements)

References 37 publications

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“…It plays an important role in the physiological and pathological processes of the nervous system. In addition, our previous studies have shown that over-activation of NMDAR by NMDA induces decreased expression of TJs in human cerebrovascular endothelial cells (HBEC-5i) and ultimately leads to the destruction of BBB function (Mao et al 2022 ; Yu et al 2022 ), while the destruction of TJ proteins in cerebrovascular endothelial cells depends on the phosphorylation of PI3K/Akt by MAPKs signaling (Cong and Kong 2020 ). Notably, modulation of the PI3K/Akt signaling pathway has been shown to be effective in endothelial TJ assembly/disassembly in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…The expression levels of ZO-1, Claudin-5, and NMDAR NR1 mRNA were calculated by the formula 2 −ΔΔCt . Primers were designed according to previous research (Mao et al 2022;Yu et al 2022). The primer sequence of NMDAR NR1 is as follows: F: AGA ATG TGA CTC CCG CAG CAATG, R: GGG CAT CCT TGT GTC GCT TGTAG.…”

Section: Quantitative Real-time Polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

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Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood–Brain Barrier Disruption and Neuronal Damage

Gong

Lao

et al. 2023

Cell Mol Neurobiol

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The disruption of the blood–brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.

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Section: Discussionmentioning

confidence: 99%

Section: Quantitative Real-time Polymerase Chain Reaction (Qrt-pcr)mentioning

confidence: 99%

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood–Brain Barrier Disruption and Neuronal Damage

Gong

Lao

et al. 2023

Cell Mol Neurobiol

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“…Circulating tPA can activate endothelial NMDARs and increase BBB permeability via the Rho signaling pathway ( 133 , 134 ). In addition, the activation of NMDARs can disrupt the BBB by activating the MEK1/2-ERK1/2 signaling pathway and upregulating MMP2/9 expression ( 135 , 136 ).…”

Section: Bbb Nmdars and Anti-nmdar Encephalitismentioning

confidence: 99%

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

Gong,

Wang,

Zhu

et al. 2023

Front. Neurol.

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Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an antibody-related autoimmune encephalitis. It is characterized by the existence of antibodies against NMDAR, mainly against the GluN1 subunit, in cerebrospinal fluid (CSF). Recent research suggests that anti-NMDAR antibodies may reduce NMDAR levels in this disorder, compromising synaptic activity in the hippocampus. Although anti-NMDAR antibodies are used as diagnostic indicators, the origin of antibodies in the central nervous system (CNS) is unclear. The blood–brain barrier (BBB), which separates the brain from the peripheral circulatory system, is crucial for antibodies and immune cells to enter or exit the CNS. The findings of cytokines in this disorder support the involvement of the BBB. Here, we aim to review the function of NMDARs and the relationship between anti-NMDAR antibodies and anti-NMDAR encephalitis. We summarize the present knowledge of the composition of the BBB, especially by emphasizing the role of BBB components. Finally, we further provide a discussion on the impact of BBB dysfunction in anti-NMDAR encephalitis.

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“…However, it has not been reported whether Akt/mTOR is directly involved in the changes of BBB function caused by NMDA induced NMDAR activation. Our previous studies found that Cav-1 knockout reduced NMDA-mediated BBB dysfunction by reducing ERK1/2 phosphorylation [ 21 ]. However, it is not very clear whether the signaling cascade after NMDAR activation affects the change of Akt/mTOR through Cav-1.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting Caveolin-1-Related Akt/mTOR Signaling Pathway Protects Against N-methyl-D-Aspartate Receptor Activation-Mediated Dysfunction of Blood–Brain Barrier in vitro

Huang,

Mao,

Nong

et al. 2023

Mol Neurobiol

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Background The aim of this study was to further explore the role of caveolin-1 (Cav-1) related Akt/mTOR signaling pathway in blood brain barrier (BBB) dysfunction caused by NMDAR activation. Methods The cell localization of NMDAR GluN1 subunit and Cav-1 was observed on human brain microvascular HBEC-5i cells after immunofluorescence double staining. The transendothelial resistance (TEER) of BBB in vitro was measured by Millicell-ERS cell resistance meter. Sodium fluorescein (SF) was used to measure the permeability of BBB in vitro. A stable Cav-1-silenced HBEC-5i cell line was established by infecting the cells with a lentivirus encoding Cav-1 shRNA. The changes of the protein and mRNA of MMP9 and Occludin induced by NMDA were detected by Western blot (WB) and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. The phosphorylated proteins of Cav-1, Akt, and mTOR were detected by WB. Results NMDAR GluN1 was expressed in the cytoplasm and part of the cell membrane of the HBEC-5i cell line. NMDAR activation decreased TEER and increased the SF of BBB in vitro. HBEC-5i cells incubated with NMDA enhanced the phosphorylation of Cav-1, Akt, and mTOR, also promoting the expression of MMP9 along with the degradation of Occludin. These effects could be reversed by pretreatment with NMDAR antagonist (MK801) or Cav-1 antagonist (Daidzein), or Akt antagonist (LY294002), respectively. Further silencing Cav-1 with LV-Cav-1-RNAi also played a similar protective effect. Conclusion Caveolin-1 (Cav-1) related Akt/mTOR signaling probably contributes to BBB dysfunction by activating NMDAR on human brain microvascular cells.

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N-methyl-D-aspartic acid increases tight junction protein destruction in brain endothelial cell via caveolin-1-associated ERK1/2 signaling

Cited by 9 publications

References 37 publications

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood–Brain Barrier Disruption and Neuronal Damage

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood–Brain Barrier Disruption and Neuronal Damage

Anti-NMDAR antibodies, the blood–brain barrier, and anti-NMDAR encephalitis

Inhibiting Caveolin-1-Related Akt/mTOR Signaling Pathway Protects Against N-methyl-D-Aspartate Receptor Activation-Mediated Dysfunction of Blood–Brain Barrier in vitro

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