Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats
Abstract Background Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist...
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doaj-87ba87c678f342ae9cbe91e957f00b6f2020-11-24T23:49:59ZengBMCJournal of Neuroinflammation1742-20942019-02-0116111510.1186/s12974-019-1432-5Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in ratsYuchun Zuo0Lei Huang1Budbazar Enkhjargal2Weilin Xu3Ocak Umut4Zachary D. Travis5Guangyu Zhang6Jiping Tang7Fei Liu8John H. Zhang9Department of Neurosurgery, Third XiangYa Hospital, Central South UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Earth and Biological Sciences, School of Medicine, Loma Linda UniversityMass Spectrometry Core Facility, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Neurosurgery, Third XiangYa Hospital, Central South UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityAbstract Background Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist bexarotene on neuroinflammation in a rat model of SAH. Methods Two hundred male Sprague-Dawley rats were used. The endovascular perforation induced SAH. Bexarotene was administered intraperitoneally at 1 h after SAH induction. To investigate the underlying mechanism, the selective RXR antagonist UVI3003 and RXR siRNA or SIRT6 inhibitor OSS128167 was administered via intracerebroventricular 1 h before SAH induction. Post-SAH assessments including SAH grade, neurological score, brain water content, Western blot, and immunofluorescence were performed. Results The endogenous RXR and sirtuin 6 (SIRT6) protein levels were increased after SAH. Bexarotene treatment significantly reduced brain edema and improved the short-/long-term neurological deficit after SAH. Mechanistically, bexarotene increased the levels of PPARγ and SIRT6; decreased the expression of phosphorylated FoxO3a (p-FoxO3a), IL-6, IL-1β, and TNF-a; and inhibited the microglia activation and neutrophils infiltration at 24 h after SAH. Either UVI3003, OSS128167, or RXR siRNA abolished the neuroprotective effects of bexarotene and its regulation on protein levels of PPARγ/SIRT6/p-FoxO3a after SAH. Conclusions The activation of RXR by bexarotene attenuated neuroinflammation and improved neurological deficits after SAH. The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway. Bexarotene may be a promising therapeutic strategy in the management of SAH patients.http://link.springer.com/article/10.1186/s12974-019-1432-5Subarachnoid hemorrhageRetinoid X receptorBexaroteneSirtuin 6NeuroinflammationBrain edema |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuchun Zuo Lei Huang Budbazar Enkhjargal Weilin Xu Ocak Umut Zachary D. Travis Guangyu Zhang Jiping Tang Fei Liu John H. Zhang |
spellingShingle |
Yuchun Zuo Lei Huang Budbazar Enkhjargal Weilin Xu Ocak Umut Zachary D. Travis Guangyu Zhang Jiping Tang Fei Liu John H. Zhang Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats Journal of Neuroinflammation Subarachnoid hemorrhage Retinoid X receptor Bexarotene Sirtuin 6 Neuroinflammation Brain edema |
author_facet |
Yuchun Zuo Lei Huang Budbazar Enkhjargal Weilin Xu Ocak Umut Zachary D. Travis Guangyu Zhang Jiping Tang Fei Liu John H. Zhang |
author_sort |
Yuchun Zuo |
title |
Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats |
title_short |
Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats |
title_full |
Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats |
title_fullStr |
Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats |
title_full_unstemmed |
Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPARγ/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats |
title_sort |
activation of retinoid x receptor by bexarotene attenuates neuroinflammation via pparγ/sirt6/foxo3a pathway after subarachnoid hemorrhage in rats |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2019-02-01 |
description |
Abstract Background Subarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high mortality and disabilities. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury. This study aimed to investigate the effects of the selective RXR agonist bexarotene on neuroinflammation in a rat model of SAH. Methods Two hundred male Sprague-Dawley rats were used. The endovascular perforation induced SAH. Bexarotene was administered intraperitoneally at 1 h after SAH induction. To investigate the underlying mechanism, the selective RXR antagonist UVI3003 and RXR siRNA or SIRT6 inhibitor OSS128167 was administered via intracerebroventricular 1 h before SAH induction. Post-SAH assessments including SAH grade, neurological score, brain water content, Western blot, and immunofluorescence were performed. Results The endogenous RXR and sirtuin 6 (SIRT6) protein levels were increased after SAH. Bexarotene treatment significantly reduced brain edema and improved the short-/long-term neurological deficit after SAH. Mechanistically, bexarotene increased the levels of PPARγ and SIRT6; decreased the expression of phosphorylated FoxO3a (p-FoxO3a), IL-6, IL-1β, and TNF-a; and inhibited the microglia activation and neutrophils infiltration at 24 h after SAH. Either UVI3003, OSS128167, or RXR siRNA abolished the neuroprotective effects of bexarotene and its regulation on protein levels of PPARγ/SIRT6/p-FoxO3a after SAH. Conclusions The activation of RXR by bexarotene attenuated neuroinflammation and improved neurological deficits after SAH. The anti-neuroinflammatory effect was at least partially through regulating PPARγ/SIRT6/FoxO3a pathway. Bexarotene may be a promising therapeutic strategy in the management of SAH patients. |
topic |
Subarachnoid hemorrhage Retinoid X receptor Bexarotene Sirtuin 6 Neuroinflammation Brain edema |
url |
http://link.springer.com/article/10.1186/s12974-019-1432-5 |
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