New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke
Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expressio...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004535 |
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| author | Yang Cai Hongfeng Gu Lu Li Xue Liu Ying Bai Ling Shen Bing Han Yungen Xu Honghong Yao |
| author_facet | Yang Cai Hongfeng Gu Lu Li Xue Liu Ying Bai Ling Shen Bing Han Yungen Xu Honghong Yao |
| author_sort | Yang Cai |
| collection | DOAJ |
| description | Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke. |
| format | Article |
| id | doaj-art-6e63ff28802f41c1a8ccd607b387bbe4 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-6e63ff28802f41c1a8ccd607b387bbe42024-12-18T08:47:20ZengElsevierPharmacological Research1096-11862024-12-01210107508New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic strokeYang Cai0Hongfeng Gu1Lu Li2Xue Liu3Ying Bai4Ling Shen5Bing Han6Yungen Xu7Honghong Yao8Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, ChinaDepartment of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, ChinaDepartment of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, ChinaDepartment of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, ChinaDepartment of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, China; Corresponding authors.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Corresponding authors.Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China; Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China; Corresponding author at: Department of Pharmacology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, China.Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke.http://www.sciencedirect.com/science/article/pii/S1043661824004535PARP7Mitochondrial dysfunctionNeuroprotective agentsPharmacologyStrokeDrug design |
| spellingShingle | Yang Cai Hongfeng Gu Lu Li Xue Liu Ying Bai Ling Shen Bing Han Yungen Xu Honghong Yao New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke Pharmacological Research PARP7 Mitochondrial dysfunction Neuroprotective agents Pharmacology Stroke Drug design |
| title | New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| title_full | New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| title_fullStr | New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| title_full_unstemmed | New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| title_short | New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| title_sort | new tiparp inhibitor rescues mitochondrial function and brain injury in ischemic stroke |
| topic | PARP7 Mitochondrial dysfunction Neuroprotective agents Pharmacology Stroke Drug design |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004535 |
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