Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation.

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Frontiers in Pharmacology Pub Date : 2024-12-12 eCollection Date: 2024-01-01 DOI:10.3389/fphar.2024.1503925
Xu Wang, Wei Huang, Hao Sun, Hua Wang, Dongxu Wang, Yongxiang Wang
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引用次数: 0

Abstract

Background: Spinal cord injury (SCI) is a neurological disease characterized by high disability and mortality rates. Tomatidine, a natural steroid alkaloid, has been evidenced to have neuroprotective properties. However, the underlying mechanisms of tomatidine in treating SCI remain ambiguous. This study aimed to illustrate the molecular mechanisms of tomatidine in modulating the inflammatory response and promoting functional rehabilitation after SCI.

Methods: Sprague-Dawley (SD) rats were used to construct an in vivo SCI model and were intraperitoneally injected with tomatidine (5, 10, or 20 mg/kg) for 7 days, followed by treatment with the nuclear factor-κB (NF-κB) pathway agonist (PMA). In addition, lipopolysaccharide (LPS)-induced PC-12 cells were used to establish an SCI cell model and were stimulated with tomatidine, PMA, or a CXCL10 inhibitor. The pathophysiological changes and neurological function were evaluated using blood-brain barrier (BBB) scoring, water content determination, hematoxylin and eosin (H&E) staining, and TUNEL assay. Levels of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, were measured. Cell proliferation, apoptosis, and the expression of C-X-C motif chemokine ligand 10 (CXCL10) were determined. Moreover, the expression of cleaved-caspase 3, caspase 3, CXCL10, p-p65, and p65 were analyzed.

Results: Our data revealed that tomatidine promoted neuronal damage recovery, reduced histopathological changes, elevated cell proliferation, and inhibited the apoptosis and inflammatory factor levels in spinal cord tissues and LPS-induced PC-12 cells. Moreover, tomatidine decreased the expression of CXCL10 in vitro and in vivo, which was accompanied by the regulation of the NF-κB pathway. However, the NF-κB pathway agonist PMA reversed the protective effect of tomatidine in vitro. PMA also enhanced the CXCL10 expression and stimulated the activation of the NF-κB pathway, as demonstrated by the upregulation of phosphorylated p65. The CXCL10 inhibitor had effects similar to tomatidine on cleaved-caspase 3 expression, CXCL10 expression, and the NF-κB pathway.

Conclusion: Tomatidine can alleviate neuronal damage in SCI by inhibiting apoptosis and inflammation through the NF-κB/CXCL10 pathway. Our findings provide a novel therapeutic target and candidate for the treatment of SCI.

番茄碱通过阻断NF-κB/CXCL10通路激活,抑制炎症反应和细胞凋亡,减轻脊髓损伤神经元损伤。
背景:脊髓损伤(SCI)是一种高致残率和死亡率的神经系统疾病。番茄碱是一种天然的类固醇生物碱,已被证明具有神经保护作用。然而,番茄碱治疗脊髓损伤的潜在机制仍不清楚。本研究旨在阐明番茄碱在脊髓损伤后调节炎症反应和促进功能康复中的分子机制。方法:采用SD大鼠建立体内脊髓损伤模型,分别腹腔注射番茄碱(5、10、20 mg/kg) 7 d,然后给予核因子-κB (NF-κB)途径激动剂(PMA)。此外,用脂多糖(LPS)诱导的PC-12细胞建立SCI细胞模型,并用番茄碱、PMA或CXCL10抑制剂刺激。采用血脑屏障(BBB)评分、水含量测定、苏木精和伊红(H&E)染色、TUNEL法评价大鼠的病理生理变化和神经功能。检测炎症因子水平,包括肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β和IL-6。检测细胞增殖、凋亡和C-X-C基序趋化因子配体10 (CXCL10)的表达。此外,还分析了cleaved-caspase 3、caspase 3、CXCL10、p-p65、p65的表达。结果:我们的数据显示,番茄碱促进脊髓组织和lps诱导的PC-12细胞的神经元损伤恢复,减少组织病理改变,增加细胞增殖,抑制凋亡和炎症因子水平。此外,番茄碱在体外和体内均能降低CXCL10的表达,并伴有NF-κB通路的调节。然而,NF-κB通路激动剂PMA在体外逆转了番茄碱的保护作用。PMA还通过磷酸化p65的上调,增强CXCL10的表达,刺激NF-κB通路的激活。CXCL10抑制剂对裂解型caspase 3表达、CXCL10表达和NF-κB通路的影响与番茄碱相似。结论:番茄碱可通过NF-κB/CXCL10通路抑制脊髓损伤神经元的凋亡和炎症,从而减轻脊髓损伤神经元的损伤。我们的发现为脊髓损伤的治疗提供了一个新的治疗靶点和候选物。
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来源期刊
Frontiers in Pharmacology
Frontiers in Pharmacology PHARMACOLOGY & PHARMACY-
CiteScore
7.80
自引率
8.90%
发文量
5163
审稿时长
14 weeks
期刊介绍: Frontiers in Pharmacology is a leading journal in its field, publishing rigorously peer-reviewed research across disciplines, including basic and clinical pharmacology, medicinal chemistry, pharmacy and toxicology. Field Chief Editor Heike Wulff at UC Davis is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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