Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway
Backgrounds: The circadian clock protein Rev-erbα is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erbα plays a key role i...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-03-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1102567/full |
| _version_ | 1797855073747861504 |
|---|---|
| author | Mingyue Sheng Mingyue Sheng Xun Chen Xun Chen Yan Yu Yan Yu Qi Wu Junping Kou Junping Kou Gangling Chen Gangling Chen |
| author_facet | Mingyue Sheng Mingyue Sheng Xun Chen Xun Chen Yan Yu Yan Yu Qi Wu Junping Kou Junping Kou Gangling Chen Gangling Chen |
| author_sort | Mingyue Sheng |
| collection | DOAJ |
| description | Backgrounds: The circadian clock protein Rev-erbα is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erbα plays a key role in the inflammation and oxidative stress, two pivotal mechanisms in the pathogenesis, progression, and recovery process of ischemic stroke. However, it remains inconclusive whether Rev-erbα activation is protective against ischemic brain damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of inflammatory and oxidative responses. Our study aimed to determine whether pharmacological activation of Rev-erbα by SR9009 protects against acute ischemic brain damage partly via Nrf2 pathway.Methods: Adult mice were pretreated with SR9009 or Nrf2 inhibitor all-trans-retinoic acid (ATRA) for 3 days prior to Sham or middle cerebral artery occlusion (MCAO) operation. After ischemia for 1 h and reperfusion for 24 h, the neurological function and cerebral infarction volume were determined, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and glutathione peroxidase (GSH-PX) activity in serum were detected by kit. The mRNA and/or protein level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), Period (Per)1, Brain and muscle arnt-like1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev-erbα, Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in cerebral cortex were detected by q-PCR and Western blot.Results: We confirmed that SR9009 activated Rev-erbα gene in the cerebral cortex under basal condition. At 24 h after reperfusion, SR9009 ameliorated acute neurological deficits, reduced infarct volume. Meanwhile, the inflammatory TNF-α, IL-1β, iNOS and MDA content levels were significant decreased, SOD and GSH-PX activity were obviously increased, which were markedly blunted (or abolished) by ATRA. SR9009 enhanced the induction of Nrf2 and its downstream target genes HO-1 and NQO1 after ischemic insult. In addition, we found that SR9009 restored Rev-erbα, Bmal1, Clock, Per1 genes expression in the cerebral cortex under ischemic condition.Conclusion: Taken together, Rev-erbα activation by SR9009 protects against ischemic stroke damage, at least, partly through Nrf2 pathway. |
| first_indexed | 2024-04-09T20:16:40Z |
| format | Article |
| id | doaj.art-8e4bf052e47d44cbb5fb1fa40e9d1709 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-09T20:16:40Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-8e4bf052e47d44cbb5fb1fa40e9d17092023-03-31T06:46:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-03-011410.3389/fphar.2023.11025671102567Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathwayMingyue Sheng0Mingyue Sheng1Xun Chen2Xun Chen3Yan Yu4Yan Yu5Qi Wu6Junping Kou7Junping Kou8Gangling Chen9Gangling Chen10Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, ChinaBackgrounds: The circadian clock protein Rev-erbα is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erbα plays a key role in the inflammation and oxidative stress, two pivotal mechanisms in the pathogenesis, progression, and recovery process of ischemic stroke. However, it remains inconclusive whether Rev-erbα activation is protective against ischemic brain damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of inflammatory and oxidative responses. Our study aimed to determine whether pharmacological activation of Rev-erbα by SR9009 protects against acute ischemic brain damage partly via Nrf2 pathway.Methods: Adult mice were pretreated with SR9009 or Nrf2 inhibitor all-trans-retinoic acid (ATRA) for 3 days prior to Sham or middle cerebral artery occlusion (MCAO) operation. After ischemia for 1 h and reperfusion for 24 h, the neurological function and cerebral infarction volume were determined, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and glutathione peroxidase (GSH-PX) activity in serum were detected by kit. The mRNA and/or protein level of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), Period (Per)1, Brain and muscle arnt-like1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev-erbα, Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in cerebral cortex were detected by q-PCR and Western blot.Results: We confirmed that SR9009 activated Rev-erbα gene in the cerebral cortex under basal condition. At 24 h after reperfusion, SR9009 ameliorated acute neurological deficits, reduced infarct volume. Meanwhile, the inflammatory TNF-α, IL-1β, iNOS and MDA content levels were significant decreased, SOD and GSH-PX activity were obviously increased, which were markedly blunted (or abolished) by ATRA. SR9009 enhanced the induction of Nrf2 and its downstream target genes HO-1 and NQO1 after ischemic insult. In addition, we found that SR9009 restored Rev-erbα, Bmal1, Clock, Per1 genes expression in the cerebral cortex under ischemic condition.Conclusion: Taken together, Rev-erbα activation by SR9009 protects against ischemic stroke damage, at least, partly through Nrf2 pathway.https://www.frontiersin.org/articles/10.3389/fphar.2023.1102567/fullcerebral ischemiaSR9009REV-erbαNrf2circadian rhythmcircadian gene |
| spellingShingle | Mingyue Sheng Mingyue Sheng Xun Chen Xun Chen Yan Yu Yan Yu Qi Wu Junping Kou Junping Kou Gangling Chen Gangling Chen Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway Frontiers in Pharmacology cerebral ischemia SR9009 REV-erbα Nrf2 circadian rhythm circadian gene |
| title | Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway |
| title_full | Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway |
| title_fullStr | Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway |
| title_full_unstemmed | Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway |
| title_short | Rev-erbα agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway |
| title_sort | rev erbα agonist sr9009 protects against cerebral ischemic injury through mechanisms involving nrf2 pathway |
| topic | cerebral ischemia SR9009 REV-erbα Nrf2 circadian rhythm circadian gene |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1102567/full |
| work_keys_str_mv | AT mingyuesheng reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT mingyuesheng reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT xunchen reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT xunchen reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT yanyu reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT yanyu reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT qiwu reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT junpingkou reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT junpingkou reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT ganglingchen reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway AT ganglingchen reverbaagonistsr9009protectsagainstcerebralischemicinjurythroughmechanismsinvolvingnrf2pathway |