The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats
Cerebral edema (CE) exerts an important effect on brain injury after traumatic brain injury (TBI). Upregulation of transient receptor potential melastatin 4 (TRPM4) in vascular endothelial cells (ECs) results in damage to capillaries and the blood-brain barrier (BBB), which is critical for the devel...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1098228/full |
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| author | Ping Ma Ning Huang Jun Tang Zunjie Zhou Jing Xu Yi Chen Maoxin Zhang Qin Huang Yuan Cheng |
| author_facet | Ping Ma Ning Huang Jun Tang Zunjie Zhou Jing Xu Yi Chen Maoxin Zhang Qin Huang Yuan Cheng |
| author_sort | Ping Ma |
| collection | DOAJ |
| description | Cerebral edema (CE) exerts an important effect on brain injury after traumatic brain injury (TBI). Upregulation of transient receptor potential melastatin 4 (TRPM4) in vascular endothelial cells (ECs) results in damage to capillaries and the blood-brain barrier (BBB), which is critical for the development of CE. Many studies have shown that 9-phenanthrol (9-PH) effectively inhibits TRPM4. The current study aimed to investigate the effect of 9-PH on reducing CE after TBI. In this experiment, we observed that 9-PH markedly reduced brain water content, BBB disruption, proliferation of microglia and astrocytes, neutrophil infiltration, neuronal apoptosis and neurobehavioral deficits. At the molecular level, 9-PH significantly inhibited the protein expression of TRPM4 and MMP-9, alleviated the expression of apoptosis-related molecules and inflammatory cytokines, such as Bax, TNF-α and IL-6, near injured tissue, and diminished serum SUR1 and TRPM4 levels. Mechanistically, treatment with 9-PH inhibited activation of the PI3K/AKT/NF-kB signaling pathway, which was reported to be involved in the expression of MMP-9. Taken together, the results of this study indicate that 9-PH effectively reduces CE and alleviates secondary brain injury partly through the following possible mechanisms: ①9-PH inhibits TRPM4-mediated Na + influx and reduces cytotoxic CE; ②9-PH hinders the expression and activity of MMP-9 by inhibiting the TRPM4 channel and decreases disruption of the BBB, thereby preventing vasogenic cerebral edema. ③9-PH reduces further inflammatory and apoptotic damage to tissues. |
| first_indexed | 2024-04-10T15:18:24Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T15:18:24Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-7ed1e538aa1d4a89aa840aefaad616432023-02-14T17:10:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-02-011410.3389/fphar.2023.10982281098228The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in ratsPing Ma0Ning Huang1Jun Tang2Zunjie Zhou3Jing Xu4Yi Chen5Maoxin Zhang6Qin Huang7Yuan Cheng8Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, ChinaCerebral edema (CE) exerts an important effect on brain injury after traumatic brain injury (TBI). Upregulation of transient receptor potential melastatin 4 (TRPM4) in vascular endothelial cells (ECs) results in damage to capillaries and the blood-brain barrier (BBB), which is critical for the development of CE. Many studies have shown that 9-phenanthrol (9-PH) effectively inhibits TRPM4. The current study aimed to investigate the effect of 9-PH on reducing CE after TBI. In this experiment, we observed that 9-PH markedly reduced brain water content, BBB disruption, proliferation of microglia and astrocytes, neutrophil infiltration, neuronal apoptosis and neurobehavioral deficits. At the molecular level, 9-PH significantly inhibited the protein expression of TRPM4 and MMP-9, alleviated the expression of apoptosis-related molecules and inflammatory cytokines, such as Bax, TNF-α and IL-6, near injured tissue, and diminished serum SUR1 and TRPM4 levels. Mechanistically, treatment with 9-PH inhibited activation of the PI3K/AKT/NF-kB signaling pathway, which was reported to be involved in the expression of MMP-9. Taken together, the results of this study indicate that 9-PH effectively reduces CE and alleviates secondary brain injury partly through the following possible mechanisms: ①9-PH inhibits TRPM4-mediated Na + influx and reduces cytotoxic CE; ②9-PH hinders the expression and activity of MMP-9 by inhibiting the TRPM4 channel and decreases disruption of the BBB, thereby preventing vasogenic cerebral edema. ③9-PH reduces further inflammatory and apoptotic damage to tissues.https://www.frontiersin.org/articles/10.3389/fphar.2023.1098228/fulltraumatic brain injurycerebral edema9-phenanthrolTRPM4MMP-9PI3K/AKT/NF-kB signaling pathway |
| spellingShingle | Ping Ma Ning Huang Jun Tang Zunjie Zhou Jing Xu Yi Chen Maoxin Zhang Qin Huang Yuan Cheng The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats Frontiers in Pharmacology traumatic brain injury cerebral edema 9-phenanthrol TRPM4 MMP-9 PI3K/AKT/NF-kB signaling pathway |
| title | The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| title_full | The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| title_fullStr | The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| title_full_unstemmed | The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| title_short | The TRPM4 channel inhibitor 9-phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| title_sort | trpm4 channel inhibitor 9 phenanthrol alleviates cerebral edema after traumatic brain injury in rats |
| topic | traumatic brain injury cerebral edema 9-phenanthrol TRPM4 MMP-9 PI3K/AKT/NF-kB signaling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1098228/full |
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