Activation of retinoid X receptor by bexarotene attenuates neuroinflammation via PPAR\u03b3/SIRT6/FoxO3a pathway after subarachnoid hemorrhage in rats

Yuchun Zuo,Lei Huang,Weilin Xu,John H Zhang,Zachary D Travis,Fei Liu,Ocak Umut,Budbazar Enkhjargal,Guangyu Zhang,Jiping Tang

doi:10.1186/s12974-019-1432-5

Yuchun Zuo, Lei Huang + Show 8 more

Open Access

https://doi.org/10.1186/s12974-019-1432-5

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Abstract

BackgroundSubarachnoid 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.MethodsTwo 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.ResultsThe 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.ConclusionsThe 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.

Highlights

Subarachnoid hemorrhage (SAH) is a devastating and life-threatening cerebrovascular disease with high mortality and disability
Blood clots were mainly distributed around the Circle of Willis and ventral brain stem after SAH induction, whereas no blood clot was observed in the sham operation (Additional file 1: Figure S1)
Our results indicated that Retinoid X receptor (RXR) activation with bexarotene might ameliorate neuroinflammation after SAH via at least partially the Peroxisome proliferator-activated receptor gamma (PPARγ)/sirtuin 6 (SIRT6)/forkhead box O3a (FoxO3a) pathway

Summary

Introduction

Subarachnoid hemorrhage (SAH) is a devastating and life-threatening cerebrovascular disease with high mortality and disability. It accounts for 5% of all stroke subtypes, whereas caused 50% case fatality after aneurysm disruption [1]. RXR has been shown to bind with peroxisome proliferator-activated receptor gamma (PPARγ) to form heterodimers [7]. PPARγ belongs to the nuclear hormone receptor superfamily and exerts an anti-inflammatory effect in many neurological diseases [8,9,10,11,12]. The regulation of the RXR/PPARγ/SIRT6/FoxO3a pathway may serve as a potential anti-neuroinflammation strategy in the setting of SAH. Retinoid X receptor (RXR) has been shown to be neuroprotective against ischemia/reperfusion injury.

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