Effects of fluoxetine on neuronal autophagy and inflammatory response in rats with subarachnoid hemorrhage by regulating the CXCR4/NLRP1 pathway
10.3760/cma.j.cn431274-20241127-01761
- VernacularTitle:氟西汀调节CXCR4/NLRP1通路对蛛网膜下腔出血大鼠神经元自噬及炎症反应的影响
- Author:
Jialu XU
1
;
Liu CUI
;
Hongxin YANG
;
Ruijuan LI
Author Information
1. 内蒙古自治区人民医院药学部，呼和浩特 010000
- Publication Type:Journal Article
- Keywords:
Fluoxetine;
Subarachnoid hemorrhage;
CXCR4/NLRP1 pathway
- From:
Journal of Chinese Physician
2025;27(11):1683-1689
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the protective effect of fluoxetine on neurons in rats with subarachnoid hemorrhage (SAH) and explore its mechanism based on the chemokine receptor 4 (CXCR4)/nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP1) pathway.Methods:Seventy-five rats were randomly divided into a normal control group and a model group. The SAH model was established by the internal carotid artery puncture method in the model group. After modeling, rats were randomly divided into the model group, fluoxetine low-, medium-, and high-dose groups, and nimodipine group, with 12 rats in each group. The fluoxetine low-, medium-, and high-dose groups were intravenously injected with fluoxetine at doses of 5, 10, and 15 mg/kg, respectively; the nimodipine group was intraperitoneally injected with nimodipine at 0.2 mg/kg; the normal control group and model group were intraperitoneally injected with an equal volume of normal saline, once a day for 7 consecutive days. The shuttle box was used to determine the number of avoidance responses and avoidance response time of rats. The water content of brain tissue and Evans blue exudation volume were calculated. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in the hippocampal tissue. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of hippocampal tissue. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA levels of CXCR4 and NLRP1 in the hippocampal tissue. Western blot was used to determine the protein levels of CXCR4, NLRP1, LC3-Ⅱ, and Beclin1 in the hippocampal tissue.Results:Compared with the normal control group, the model group had a lower number of avoidance responses, lower levels of SOD, CAT, GSH, CXCR4 mRNA, CXCR4, LC3-Ⅱ, and Beclin1 protein in the hippocampal tissue (all P<0.05); while the avoidance response time, brain water content, Evans blue exudation volume, levels of IL-6, TNF-α, MDA, and mRNA and protein levels of NLRP1 in the hippocampal tissue were higher (all P<0.05). Compared with the model group, the fluoxetine groups (all doses) and nimodipine group had a higher number of avoidance responses, higher levels of SOD, CAT, GSH, CXCR4 mRNA, CXCR4, LC3-Ⅱ, and Beclin1 protein in the hippocampal tissue (all P<0.05); while the avoidance response time, brain water content, Evans blue exudation volume, levels of IL-6, TNF-α, MDA, and mRNA and protein levels of NLRP1 in the hippocampal tissue were lower (all P<0.05); moreover, the changes in various indicators were more significant with the increase of fluoxetine dose. HE staining results showed that there were no pathological changes in the hippocampal tissue of the normal control group; in the model group, the number of hippocampal neurons decreased, nuclei were pycnotic, and cell arrangement was irregular. Compared with the model group, the number of hippocampal neurons increased, cell arrangement was regular, and hippocampal pathology was significantly restored in the fluoxetine groups (all doses) and nimodipine group. Conclusions:Fluoxetine can significantly alleviate the pathological progression of cerebral edema, repair neuronal damage, improve neurological function, and regulate mitochondrial autophagy in SAH rats, whose mechanism may be related to the regulation of the CXCR4/NLRP1 pathway.
