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Inhibition of P2X4 and P2X7 receptors improves histological and behavioral outcomes after experimental traumatic brain injury in rats
被引:7
作者:
Kobayashi, Masato
[1
]
Moro, Nobuhiro
[1
,2
]
Yoshino, Atsuo
[1
]
Kumagawa, Takahiro
[1
]
Shijo, Katsunori
[1
]
Maeda, Takeshi
[1
]
Oshima, Hideki
[1
]
机构:
[1] Nihon Univ, Dept Neurol Surg, Div Neurosurg, Sch Med, 30-1 Oyaguchi Kamimachi,Itabashi Ku, Tokyo 1738610, Japan
[2] Honjo Gen Hosp, Dept Neurol Surg, Saitama 3670031, Japan
关键词:
adenosine triphosphate;
gliotransmitter;
microglia;
purinergic receptors;
traumatic brain injury;
REACTIVE ASTROCYTES;
AXONAL INJURY;
ACTIVATION;
CYTOKINES;
GLUTAMATE;
MICROGLIA;
STRIATUM;
PROTECTS;
ABLATION;
MICE;
D O I:
10.3892/etm.2023.12077
中图分类号:
R-3 [医学研究方法];
R3 [基础医学];
学科分类号:
1001 ;
摘要:
Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naive group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury.
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页数:11
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