TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway
Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signal...
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| Format: | Article |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1080438/full |
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| author | Zeyang Li Zeyang Li Minghui Zhao Minghui Zhao Xiaoqian Zhang Yiran Lu Yang Yang Yang Yang Yalong Xie Yalong Xie Zhimiao Zou Zhimiao Zou Liang Zhou Liang Zhou Runshi Shang Runshi Shang Limin Zhang Limin Zhang Fengchao Jiang Dunfeng Du Dunfeng Du Ping Zhou Ping Zhou |
| author_facet | Zeyang Li Zeyang Li Minghui Zhao Minghui Zhao Xiaoqian Zhang Yiran Lu Yang Yang Yang Yang Yalong Xie Yalong Xie Zhimiao Zou Zhimiao Zou Liang Zhou Liang Zhou Runshi Shang Runshi Shang Limin Zhang Limin Zhang Fengchao Jiang Dunfeng Du Dunfeng Du Ping Zhou Ping Zhou |
| author_sort | Zeyang Li |
| collection | DOAJ |
| description | Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI.Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-κB and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry.Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-κB and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity.Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses. |
| first_indexed | 2024-04-13T04:21:13Z |
| format | Article |
| id | doaj.art-54268371274e454eb523743c1e532332 |
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| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T04:21:13Z |
| publishDate | 2022-12-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-54268371274e454eb523743c1e5323322022-12-22T03:02:46ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10804381080438TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathwayZeyang Li0Zeyang Li1Minghui Zhao2Minghui Zhao3Xiaoqian Zhang4Yiran Lu5Yang Yang6Yang Yang7Yalong Xie8Yalong Xie9Zhimiao Zou10Zhimiao Zou11Liang Zhou12Liang Zhou13Runshi Shang14Runshi Shang15Limin Zhang16Limin Zhang17Fengchao Jiang18Dunfeng Du19Dunfeng Du20Ping Zhou21Ping Zhou22Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaWuhan Yangtze International School, Wuhan International Educational Center, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaAcademy of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaInstitute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaKey Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, ChinaBackground: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-κB signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI.Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-κB and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry.Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-κB and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity.Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses.https://www.frontiersin.org/articles/10.3389/fphar.2022.1080438/fullTJ-M2010-5drugcerebral ischemia-reperfusion injuryneuroinflammationMyd88 inhibitor |
| spellingShingle | Zeyang Li Zeyang Li Minghui Zhao Minghui Zhao Xiaoqian Zhang Yiran Lu Yang Yang Yang Yang Yalong Xie Yalong Xie Zhimiao Zou Zhimiao Zou Liang Zhou Liang Zhou Runshi Shang Runshi Shang Limin Zhang Limin Zhang Fengchao Jiang Dunfeng Du Dunfeng Du Ping Zhou Ping Zhou TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway Frontiers in Pharmacology TJ-M2010-5 drug cerebral ischemia-reperfusion injury neuroinflammation Myd88 inhibitor |
| title | TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway |
| title_full | TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway |
| title_fullStr | TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway |
| title_full_unstemmed | TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway |
| title_short | TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway |
| title_sort | tj m2010 5 a novel cns drug candidate attenuates acute cerebral ischemia reperfusion injury through the myd88 nf κb and erk pathway |
| topic | TJ-M2010-5 drug cerebral ischemia-reperfusion injury neuroinflammation Myd88 inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1080438/full |
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