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Original Research | Open Access

Inhibition of P2X7R alleviates neuroinflammation and brain edema after traumatic brain injury by suppressing the NF-κB/NLRP3 inflammasome pathway

Bingyan Taoa,b,c,1Jie Peid,1Hao LieGuochao YangfXudong Shia,cZehan ZhanggHui WanghZhou ZhengiYuyang Liuc,j,k( )Jun Zhanga( )
Department of Neurosurgery, the First Medical Centre, Chinese PLA General Hospital, Beijing 100853, China
Department of Neurosurgery, 961th Hospital of Joint Logistics Support Force, Qiqihar 161000, Heilongjiang, China
Medical School of Chinese PLA, Beijing 100853, China
Institute of Military Cognition and Brain Sciences, Beijing, 100850, China
Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China
Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210061, Jiangsu, China
Department of Neurosurgery, PLA Air Force Hospital of Southern Theatre Command, Guangzhou,510602, Guangdong, China
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China
Department of Emergency, 920th Hospital of Joint Logistics Support Force, Kunming 650032, Yunnan, China
Department of Neurosurgery, 920th Hospital of Joint Logistics Support Force, Kunming 650032, Yunnan, China
Chinese PLA Spinal Cord Injury Treatment Center, Kunming 650032, Yunnan, China

1 These authors contributed equally to this work.

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Abstract

Background

Purinergic ligand-gated ion channel 7 receptor (P2X7R) is an ATP-gated cationic channel. It plays an important role in central nervous system diseases such as cerebral hemorrhage and Parkinson's disease, and is closely related to neuroinflammatory reactions associated with disease progression. In the present study, we evaluated the role of P2X7R in neuroinflammation and brain edema after traumatic brain injury (TBI). We also investigated the related mechanisms and potential therapeutic drugs.

Methods

In the in vivo experiments, C57BL/6 mice were randomly divided into four groups: Sham, TBI, TBI + A438079, or TBI + MCC950. The TBI model was constructed via controlled cortical impact, and mice then received saline, A438079, or MCC950 injections. Morphological damage to the brains of mice was observed by Nissl staining. Morphological and quantitative changes in microglia as well as P2X7R expression were observed via immunofluorescence. The water content of brain tissue was evaluated using the brain dry/wet weight ratio. In the in vitro experiments, lipopolysaccharides were used to stimulate murine microglial BV2 cells into an inflammatory activation state. The expression of P2X7R, interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, nuclear factor kappa-B (NF-κB), and NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasomes in BV2 cells was analyzed using enzyme-linked immunosorbent assay and Western blot. Moreover, an indirect co-culture technique was used to evaluate the effects of the neuroinflammatory model of BV2 cells on tight junction protein expression in mouse brain microvascular endothelial bEnd.3 cells.

Results

Levels of P2X7R, IL-1β, IL-6, IL-12, TNF-α, NF-κB, and NLRP3 inflammasomes were significantly higher in the TBI group than in the Sham group. TBI also increased the brain edema degree and tight junction protein expression levels. By targeting P2X7R (with A438079) or NLRP3 (with MCC950), we were able to inhibit neuroinflammation and alleviate brain edema.

Conclusions

Targeting P2X7R may help to reduce neuroinflammation and brain edema secondary to acute TBI by inhibiting the NF-κB/NLRP3 inflammasome pathway. P2X7R may be an innovative therapeutic target in TBI.

Journal of Neurorestoratology
Article number: 100106
Cite this article:
Tao B, Pei J, Li H, et al. Inhibition of P2X7R alleviates neuroinflammation and brain edema after traumatic brain injury by suppressing the NF-κB/NLRP3 inflammasome pathway. Journal of Neurorestoratology, 2024, 12(2): 100106. https://doi.org/10.1016/j.jnrt.2024.100106

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Received: 21 November 2023
Revised: 07 January 2024
Accepted: 18 January 2024
Published: 29 February 2024
© 2024

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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