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Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia

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Abstract

Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague–Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen–glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen–glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.

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Data Availability

The datasets used and/or analyzed during this study are available from the corresponding authors on reasonable request.

Abbreviations

ATP:

Adenosine triphosphate

BBB:

Blood-brain barrier

BBG:

Brilliant Blue G

CA/CPR:

Cardiac arrest/cardiopulmonary resuscitation

DAMPs:

Danger-associated molecular patterns

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

GFAP:

Glial fibrillary acidic protein

GLB:

Glibenclamide

GLM:

Glimepiride

GLZ:

Gliclazide

Iba-1:

Ionized calcium-binding adapter molecule-1

IL-1β:

Interleukin-1β

K2P family:

Two-pore domain K+ channel family

Kv family:

Voltage-gated K+ channel family

LPS:

Lipopolysaccharides

MAP:

Mean arterial pressure

MAP-2:

Microtubule-associated protein 2

NDSs:

Neurologic deficit scores

NeuN:

Neuronal nuclei

NF-κB:

Nuclear factor kappa-B

NLRP3:

Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3

OGD/R:

Oxygen-glucose deprivation/reperfusion

PFA:

Paraformaldehyde

pro-caspase-1:

Precursor of caspase-1

pro-IL-1β:

Precursor of IL-1β

P2X7R:

P2X7 receptor

qRT-PCR:

Quantitative real-time polymerase chain reaction

ROSC:

Return of spontaneous circulation

Sp-1:

Specificity protein 1

SUR1-TRPM4:

Sulfonylurea receptor 1-transient receptor potential M4

THIK1:

Tandem pore domain halothane-inhibited K+ channel 1

TLR:

Toll-like receptor

TWIK1:

Two-pore domain weak inwardly rectifying K+ channel 1

9-Ph:

9-Phenanthrol

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Acknowledgements

We thank the central laboratory of Southern Medical University for technical assistance in immunofluorescence capture under the confocal microscope.

Funding

This work was supported by the National Key R&D Program of China (No. 2017YFC1307500), National Natural Science Foundation of China (No. 81701294 & 82072133 & 81871030), and Guangdong Basic and Applied Basic Research Foundation (2019A1515011446 & 2021A1515010922).

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  1. Yihua He and Yuan Chang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China

    Yihua He, Yuan Chang, Yuqin Peng, Juan Zhu, Kewei Liu, Jiancong Chen, Yongming Wu, Zhong Ji, Zhenzhou Lin, Shengnan Wang, Sohan Gupta, Nailiang Zang, Suyue Pan & Kaibin Huang

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  1. Yihua He
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Contributions

Y.H. and Y.C. performed all the experiments and wrote the manuscript. Y.P., J.Z., K.L., J.C., Y.W., Z.J., Z.L., S.W., S.G., and N.Z. completed the statistical analysis. S.P. and K.H. designed, guided the experiments, and critically revised the manuscript.

Corresponding authors

Correspondence to Suyue Pan or Kaibin Huang.

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All animal experiments in this study were approved by Animal Care and Use Committee of Nanfang Hospital, Southern Medical University (Guangzhou, China).

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He, Y., Chang, Y., Peng, Y. et al. Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia. Mol Neurobiol 59, 6590–6607 (2022). https://doi.org/10.1007/s12035-022-02998-x

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