Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation
BackgroundSpinal 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 st...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-12-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1503925/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846127294775558144 |
|---|---|
| author | Xu Wang Xu Wang Wei Huang Hao Sun Hua Wang Dongxu Wang Yongxiang Wang Yongxiang Wang |
| author_facet | Xu Wang Xu Wang Wei Huang Hao Sun Hua Wang Dongxu Wang Yongxiang Wang Yongxiang Wang |
| author_sort | Xu Wang |
| collection | DOAJ |
| description | BackgroundSpinal 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.MethodsSprague–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.ResultsOur 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.ConclusionTomatidine 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. |
| format | Article |
| id | doaj-art-3cb3bbf674104063942290ba742470b0 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-3cb3bbf674104063942290ba742470b02024-12-12T04:29:43ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-12-011510.3389/fphar.2024.15039251503925Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activationXu Wang0Xu Wang1Wei Huang2Hao Sun3Hua Wang4Dongxu Wang5Yongxiang Wang6Yongxiang Wang7The Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, ChinaDepartment of Trauma Surgery, Northern Jiangsu People’s Hospital, Yangzhou, ChinaHealth Management Center, Northern Jiangsu People’s Hospital, Yangzhou, ChinaDepartment of Trauma Surgery, Northern Jiangsu People’s Hospital, Yangzhou, ChinaDepartment of Trauma Surgery, Northern Jiangsu People’s Hospital, Yangzhou, ChinaSchool of Grain Science and Technology, Jiangsu University of Science and Technology, Zhenjiang, ChinaThe Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, ChinaDepartment of Trauma Surgery, Northern Jiangsu People’s Hospital, Yangzhou, ChinaBackgroundSpinal 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.MethodsSprague–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.ResultsOur 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.ConclusionTomatidine 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.https://www.frontiersin.org/articles/10.3389/fphar.2024.1503925/fulltomatidinespinal cord injuryneuronal damagenuclear factor-κB/C-X-C motif chemokine ligand 10 pathwayapoptosis |
| spellingShingle | Xu Wang Xu Wang Wei Huang Hao Sun Hua Wang Dongxu Wang Yongxiang Wang Yongxiang Wang Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation Frontiers in Pharmacology tomatidine spinal cord injury neuronal damage nuclear factor-κB/C-X-C motif chemokine ligand 10 pathway apoptosis |
| title | Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation |
| title_full | Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation |
| title_fullStr | Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation |
| title_full_unstemmed | Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation |
| title_short | Tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the NF-κB/CXCL10 pathway activation |
| title_sort | tomatidine relieves neuronal damage in spinal cord injury by inhibiting the inflammatory responses and apoptosis through blocking the nf κb cxcl10 pathway activation |
| topic | tomatidine spinal cord injury neuronal damage nuclear factor-κB/C-X-C motif chemokine ligand 10 pathway apoptosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1503925/full |
| work_keys_str_mv | AT xuwang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT xuwang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT weihuang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT haosun tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT huawang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT dongxuwang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT yongxiangwang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation AT yongxiangwang tomatidinerelievesneuronaldamageinspinalcordinjurybyinhibitingtheinflammatoryresponsesandapoptosisthroughblockingthenfkbcxcl10pathwayactivation |