Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury

He, Junchi; Liu, Han; Zhong, Jian; Guo, Zongduo; Wu, Junqi; Zhang, Hongrong; Huang, Zhijian; Jiang, Li; Li, Hui; Zhang, Zhaosi; Liu, Liu; Wu, Yue; Qi, Lingjun; Sun, Xiaochuan; Cheng, Chung–Ying

doi:10.1016/j.nbd.2018.06.003

Cited by 40 publications

(28 citation statements)

References 41 publications

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“…were used, revealing that microglia/macrophages were signi cantly polarized into the classical activation phenotype (M1) after ICH. This nding was consistent with a previous study [17], as our data indicated that the activation of RXR-α could inhibit M1 activation and driving microglia/macrophages towards the M2 phenotype while PPAR-γ inhibitor GW9662 reversed these effects. In the rest of this study, we further explored the role of PPAR-γ in neurological function and hematoma volume in response to RXR-α activation after ICH.…”

Section: Discussionsupporting

confidence: 93%

“…We noted the enhanced translocation to the nucleus of RXR-α and PPAR-γ after injury. Our ndings were consistent with a previous study that reported enhanced translocation of RXR-α and PPAR-γ after traumatic brain injury [17]. Several studies on intracellular RXR shuttling were performed, showing that nuclear translocation of RXR was triggered by in ammatory cytokines such as IL-1β, IL-6, and TNF-α [40,41].…”

Section: Discussionsupporting

confidence: 93%

“…Additionally, PPAR-γ activation mediates the transcription of downstream genes, such as ABCA1 and Cd36, which are also considered as biomarkers of scavenger receptors that contribute to the phagocytic ability of microglia/macrophages [3,31]. A previous study has shown that the activation of the RXR/PPAR heterodimer exerts neuroprotective effects by modulating microglia polarization [17]. Given the involvement of RXR-α and PPAR-γ in microglia/macrophages-type cell polarization and differentiation, we assessed the expression of M1/M2 markers in microglia/macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…bexarotene solution (5 mg/kg) or an equal volume of vehicle or bexarotene solution (5 mg/kg) + GW9662 solution (4 mg/kg) was administered intraperitoneally 1 h after ICH for the rst time, followed by daily injections until sacri ce. The dosage and time points of bexarotene and GW9662 were based on a previous study [21,22].…”

Section: Drug Administrationmentioning

confidence: 99%

“…Current studies reported that activation of RXR-α, which forms a heterodimer with peroxisome proliferator-activated receptor-γ (PPAR-γ), was implicated as a promising treatment for Alzheimer's disease [15,16]. Notably, a recent study has demonstrated that the activation of RXR-α may promote the nuclear accumulation and transcriptional activity of PPAR-γ, therefore modulating microglia polarization in traumatic brain injury [17]. However, the role of RXR-α in the pathological process following ICH has not yet been fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Chen

Zhou

et al. 2020

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Background: Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH.Methods: ICH mouse models were established by the stereotactic injection of autologous arterial blood into the right basal ganglia. The selective RXR-α agonist bexarotene and peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 were administered intraperitoneally at 1 h after ICH. Post-ICH assessments were in the form of magnetic resonance imaging scans, neurological tests, Western blotting, enzyme-linked immunosorbent assays, and immunofluorescence. Results: Pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in the microglia/macrophages, neurons, and astrocytes. Mechanically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, alongside reducing neuroinflammation by modulating microglia/macrophages reprograming into the M2 phenotype from M1 phenotype. However, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662.Conclusion: The pharmacological activation of RXR-α conferred robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Drug Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Chen

Zhou

et al. 2020

Preprint

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Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions

2022

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The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats

et al. 2020

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Rationale The nuclear receptor retinoid X receptor (RXR) belongs to a nuclear receptor superfamily that modulates diverse functions via homodimerization with itself or several other nuclear receptors, including PPARα. While the activation of PPARα by natural or synthetic agonists regulates the sleep-wake cycle, the role of RXR in the sleep modulation is unknown.Objectives We investigated the effects of bexarotene (Bexa, a RXR agonist) or UVI 3003 (UVI, a RXR antagonist) on sleep, sleep homeostasis, levels of neurochemical related to sleep modulation, and c-Fos and NeuN expression.Methods The sleep-wake cycle and sleep homeostasis were analyzed after application of Bexa or UVI. Moreover, we also evaluated whether Bexa or UVI could induce effects on dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine contents, collected from either the nucleus accumbens or basal forebrain. In addition, c-Fos and NeuN expression in the hypothalamus was determined after Bexa or UVI treatments.Results Systemic application of Bexa (1 mM, i.p.) attenuated slow-wave sleep and rapid eye movement sleep. In addition, Bexa increased the levels of dopamine, serotonin, norepinephrine epinephrine, adenosine, and acetylcholine sampled from either the nucleus accumbens or basal forebrain. Moreover, Bexa blocked the sleep rebound period after total sleep deprivation, increased in the hypothalamus the expression of c-Fos, and decreased NeuN activity. Remarkably, UVI 3003 (1 mM, i.p.) induced opposite effects in sleep, sleep homeostasis, neurochemicals levels, and c-Fos and NeuN activity. ConclusionsThe administration of RXR agonist or antagonist significantly impaired the sleep-wake cycle and exerted effects on the levels of neurochemicals related to sleep modulation. Moreover, Bexa or UVI administration significantly affected c-Fos and NeuN expression in the hypothalamus. Our findings highlight the neurobiological role of RXR on sleep modulation.

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Bexarotene protects against neurotoxicity partially through a PPARγ-dependent mechanism in mice following traumatic brain injury

Cited by 40 publications

References 41 publications

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Therapeutic modulation of JAK-STAT, mTOR, and PPAR-γ signaling in neurological dysfunctions

The retinoid X receptor: a nuclear receptor that modulates the sleep-wake cycle in rats

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