NMDA mediates disruption of blood-brain barrier permeability via Rho/ROCK signaling pathway

Yu, Y. L.; Wu, Yu; Wei, Junxiang; Huang, Feizhou; Mao, Fengping; Nong, Weidong; Cao, Xiaoli; Huang, Wen Cheng

doi:10.1016/j.neuint.2022.105278

Cited by 11 publications

(10 citation statements)

References 47 publications

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“…Through this interaction, tPA, an important component of the pathophysiology of many neurovascular and neurodegenerative disorders [ 101 , 107 , 217 ], promotes NMDAR over-activation and subsequent toxicity on the BBB and neurons [ 46 ]. In inflammatory conditions, the presence of tPA potentiates vascular endothelial NMDAR activity close to the tight-junctions and the Rho/ROCK pathway leading to an increase in BBB permeability leading to the infiltration of immune cells into the brain [ 111 , 112 , 114 , 119 ]. Glunomab is counteracting both the neuroinflammation directly linked to the increase of the permeability of the BBB and the following transmigration of toxic inflammatory cells into the brain parenchyma and the associated excitotoxicity mechanisms on neuronal synapses.…”

Section: Discussionmentioning

confidence: 99%

“…The tight junction-associated spinal cord endothelial NMDARs contain GluN1, GluN2B, and GluN3A subunits [ 111 ]. The intracellular pathways that mediate the toxic effects of NMDAR activation in endothelial cells include the production of ROS and NO, increased intracellular Ca 2+ [ 108 ], and activation of intracellular kinases such as RhoA kinase [ 111 , 119 ]. On the other hand, excessive glutamate release can lead to synaptic damage and excitotoxicity in neurons coupled with a demyelination process, possibly by inducing excitotoxic death in myelinating oligodendrocytes [ 114 ].…”

Section: Cns Diseases and Nmdar Dysfunctionsmentioning

confidence: 99%

“…NMDAR signaling induces downstream pathway activation, involving Rho proteins such as Ras homolog family member A (RhoA), Ras homolog family member B (RhoB) and Rho-associated protein kinase (ROCK) [ 111 , 119 , 120 ]. Rho proteins are key molecules interacting with a large number of targets and directly influencing cytoskeleton rearrangement, cell mobility, and cellular contractility that are disturbed during inflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Seillier

Lesept

Toutirais

et al. 2022

IJMS

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The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Cns Diseases and Nmdar Dysfunctionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Seillier

Lesept

Toutirais

et al. 2022

IJMS

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show abstract

“…NMDARs may be activated to induce a breakdown of the BBB ( 132 ). Overactivation of NMDARs can alter the expression of TJs, affecting BBB permeability ( 133 ). Circulating tPA can activate endothelial NMDARs and increase BBB permeability via the Rho signaling pathway ( 133 , 134 ).…”

Section: Bbb Nmdars and Anti-nmdar Encephalitismentioning

confidence: 99%

“…Overactivation of NMDARs can alter the expression of TJs, affecting BBB permeability ( 133 ). 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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“Baihui” (DU20)‐penetrating “Qubin” (GB7) acupuncture on blood–brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK II/MLC 2 signaling pathway

Zhang,

Zheng,

et al. 2024

Anim Models and Exp Med

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BackgroundBlocking the RhoA/ROCK II/MLC 2 (Ras homolog gene family member A/Rho kinase II/myosin light chain 2) signaling pathway can initiate neuroprotective mechanisms against neurological diseases such as stroke, cerebral ischemia, and subarachnoid hemorrhage. Nevertheless, it is not clear whether and how disrupting the RhoA/ROCK II/MLC 2 signaling pathway changes the pathogenic processes of the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH). The present investigation included the injection of rat caudal vein blood into the basal ganglia area to replicate the pathophysiological conditions caused by ICH.MethodsScalp acupuncture (SA) therapy was performed on rats with ICH at the acupuncture point “Baihui”‐penetrating “Qubin,” and the ROCK selective inhibitor fasudil was used as a positive control to evaluate the inhibitory effect of acupuncture on the RhoA/ROCK II/MLC 2 signaling pathway. Post‐assessments included neurological deficits, brain edema, Evans blue extravasation, Western blot, quantitative polymerase chain reaction, and transmission electron microscope imaging.ResultsWe found that ROCK II acts as a promoter of the RhoA/ROCK II/MLC 2 signaling pathway, and its expression increased at 6 h after ICH, peaked at 3 days, and then decreased at 7 days after ICH, but was still higher than the pre‐intervention level. According to some experimental results, although 3 days is the peak, 7 days is the best time point for acupuncture treatment. Starting from 6 h after ICH, the neurovascular structure and endothelial cell morphology around the hematoma began to change. Based on the changes in the promoter ROCK II, a 7‐day time point was selected as the breakthrough point for treating ICH model rats in the main experiment. The results of this experiment showed that both SA at “Baihui”‐penetrating “Qubin” and treatment with fasudil could improve the expression of endothelial‐related proteins by inhibiting the RhoA/ROCK II/MLC 2 signaling pathway and reduce neurological dysfunction, brain edema, and BBB permeability in rats.ConclusionThis study found that these experimental data indicated that SA at “Baihui”‐penetrating “Qubin” could preserve BBB integrity and neurological function recovery after ICH by inhibiting RhoA/ROCK II/MLC 2 signaling pathway activation and by regulating endothelial cell–related proteins.

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NMDA mediates disruption of blood-brain barrier permeability via Rho/ROCK signaling pathway

Cited by 11 publications

References 47 publications

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

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

“Baihui” (DU20)‐penetrating “Qubin” (GB7) acupuncture on blood–brain barrier integrity in rat intracerebral hemorrhage models via the RhoA/ROCK II/MLC 2 signaling pathway

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