Umbelliferone ameliorates cerebral ischemia–reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome

doi:10.1016/j.neulet.2015.06.016

Neuroscience Letters

Volume 600, 23 July 2015, Pages 182-187

https://doi.org/10.1016/j.neulet.2015.06.016 Get rights and content

Highlights

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Umbelliferone notably ameliorates cerebral ischemia–reperfusion injury.
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Umbelliferone suppresses expression of NLRP3 inflammasome.
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Umbelliferone attenuates cerebral ischemia–reperfusion injury via regulating PPARγ.

Abstract

Umbelliferone (UMB), a natural antioxidant belonging to coumarin derivatives, is able to cross the blood-brain barrier and protect neuronal cells from death. Here we aimed to investigate the effects of UMB in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Pretreatment with UMB (15 and 30 mg/kg) for 7 consecutive days ameliorated the neurological outcomes, infarct volume and brain edema in brains of MCAO rats. Our results provided evidence that UMB significantly protected neuronal cells against cerebral ischemia reperfusion-induced injury. Furthermore, UMB treatment could inhibited the level of oxidative stress and the production of inflammatory cytokines in brain tissues of MCAO rats. In addition, UMB significantly upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), which exhibited neuroprotective effects in neurodegenerative disease. UMB treatment also suppressed NLRP3 inflammasome activation via reducing expression of Thiredoxin-interactive protein (TXNIP). These results suggest that UMB may have beneficial effects for neuroprotection against focal cerebral ischemic partly through the inhibition of TXNIP/NLRP3 inflammasome and activation of PPAR-γ.

Section snippets

Introduction:

Ischemic stroke is the leading cause of brain injury which is characterized as high incidence, high morbidity and high mortality [1]. Ischemic stroke can induce many damaging effects, such as disruption of blood-brain barrier, brain edema, which cause brain injury [2]. Prevention of ischemia/reperfusion injury is becoming an important issue in Ischemic stroke treatment. The mechanism of ischemic injury is complex, the currently acknowledged theories include excitotoxicity, cailcium overload,

Materials

Umbelliferone (purity ≥ 98%) (Nanjing Zelang Medical Technology Co., Ltd., China), 2,3,5-triphenyltetrazolium chloride (TTC) (Amresco, USA), SOD and MDA assay kits (Nanjing Jiancheng Bioengineering Institute, China), IL-1β and IL-18 ELISA kits (Shenzhen Dakewe Biotech Co., Ltd., China), Bicinchoninic acid (BCA) kit (Beyotime Institute of Biotechnology Co., Ltd., Shanghai, China). Antibodies used in Western blot analysis: anti-caspase-1 (ab108362) were purchased from Abcam (Cambridge, MA, USA);

Effects of UMB on the neurological defect scores and brain water content in rats

As shown in Fig. 1A, there were no neurological deficit in Sham group, and the neurological function scores of MCAO group were significantly higher than Sham group. Compared with the model, the scores in groups pretreated with UMB (15 and 30 mg/kg) showed a significantly decreasing trend [F(3,36) = 33.86, p < 0.01].

The BWC is measured after 22 h of reperfusion with data presented in Fig. 1B. The BWC was significantly increased in MCAO group compared with the sham and significantly decreased in

Discussion

In this study, we evaluated the effects of pretreatment with UMB in a rat model of cerebral ischemic-reperfusion for the first time and found that UMB pretreatment improved neurological outcomes, reduced infarct volume and brain edema.

The mechanism of the neuroprotective effects of UMB in the brain tissue of rats after MCAO was discussed. Our results showed that UMB treatment alleviated brain injury through the inhibition of the level of IL-1β and IL-18 in brain tissues, which resulted in

Conclusions

Our results provide evidence that the chronic exposure to MCAO induced cerebral damage through oxidative stress and inflammatory response. Pretreatment with UMB exhibited neuroprotective effects in ischemia/reperfusion-induced brain injury. This effect of UMB may be partly related with inhibition of NLRP3 inflammasome in the brain and upregulation of PPAR-γ expression, suggesting the prevention effect of UMB for the Ischemic stroke.

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This study is supported by the Fundamental Research Funds for the Central Universities (Program No. JKZD2013009) and the project in our department is funded by Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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HIV-associated comorbidities, such as ischemic stroke, are prevalent in people with HIV (PWH). Several studies both in animal models and humans have revealed an association between activation of the inflammasome in HIV-1 infection and stroke. The gut microbiota is an important component in controlling neuroinflammation in the CNS. It has also been proposed to be involved in the pathobiology of HIV-1 infection, and has been associated with an increase in activation of the inflammasome. In this review, we provide an overview of the microbiota–gut–inflammasome–brain axis, focusing on the NLRP3 inflammasome and dysregulation of the microbiome as risk factors that may contribute to the outcome of ischemic stroke and recovery in PWH. We also focus on the potential of targeting the NLRP3 inflammasome as a novel therapeutic approach for PWH who are at risk of developing cerebrovascular diseases.
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Citation Excerpt :
Mitochondrial dysfunction-induced oxidative stress augments activation of NLRP3 at the post-translational level (Zhou et al., 2011) and at the transcriptional level via increased NF-κB activation in response to ischemia (Rubartelli, 2012; Minutoli et al., 2016). NLRP3 upregulates inflammatory response (Cai et al.) and provokes IL-1β and IL-18 release (Wang et al., 2015). It has been previously demonstrated that PPARγ agonists enhanced antioxidant capacity and reduced post-ischemic neuronal cell death, most likely through inhibiting COX-2 production in neuronal cells (Miglio et al., 2009).
Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.
Coumarins derivatives and inflammation: Review of their effects on the inflammatory signaling pathways
2022, European Journal of Pharmacology
Natural and synthetic coumarins have been extensively described in the literature as effective drugs with several pharmacological activities. Many valuable publications have shown the anti-inflammatory potential of these compounds suggesting that coumarins could be an interesting scaffold for developing new therapeutic anti-inflammatory agents. However, despite the continuous efforts of research in this field, no major breakthrough was yet achieved and only a few coumarin-like drugs are commercially available.
In the present article, we reviewed the most relevant studies conducted in the last two decades (2000–2021) and presenting evidence for the anti-inflammatory mechanisms of coumarins. The review provides a comprehensive survey of scientific research revealing through multiple in vitro and in vivo models the effect of natural and synthetic coumarins on components of the Toll-like receptors (TLR), Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Inflammasomes, mitogen-activated protein kinase (MAPK), nuclear factor- κ-light-chain-enhancer of activated B cells (NF- κB) and transforming growth factor-β/small mothers against decapentaplegic (TGF-β/SMAD) pathways.
Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis
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Pyroptosis mediated by nucleotide-binding oligomerization domain (NOD)-like receptor 3 (NLRP3) inflammasome is implicated in cerebral ischemia/reperfusion (I/R) injury. Ginsenoside Rd (Rd), a monomer component of Panax ginseng and Panax notoginseng, is reported to confer neuroprotection in brain injury models. However, the role of pyroptosis in Rd-mediated neuroprotection following cerebral I/R has not been investigated. We aimed to confirm the neuroprotective function and underlying mechanisms of Rd on pyroptosis after cerebral I/R using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male C57BL/6 mice, and oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary cortical neurons. MicroRNA-139-5p (miR-139-5p) downregulation, forkhead box transcription factor O1 (FOXO1) and Kelch-like ECH-associated protein 1 (Keap1) upregulation, nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant pathway inactivation, reactive oxygen species (ROS)-driven thioredoxin-interacting protein (TXNIP) over-expression, and NLRP3 inflammasome activation-induced pyroptosis were observed in ischemic cortical tissues and primary neurons under MCAO/R and OGD/R induction. More importantly, Rd upregulated miR-139-5p to inhibit FoxO1 which regulates Keap1 transcriptional activity, and subsequently activates the Nrf2 antioxidant pathway, resulting in attenuation of ROS/TXNIP/NLRP3 inflammasome axis-driven pyroptosis in these animal and cell models. In summary, an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis may be the mechanism by which Rd attenuates ischemic stroke.

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Research articleUmbelliferone ameliorates cerebral ischemia–reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome

Highlights

Abstract

Section snippets

Introduction:

Materials

Effects of UMB on the neurological defect scores and brain water content in rats

Discussion

Conclusions

Conflict of interest

Acknowledgments

Ageing Res. Rev.

Alcohol

Cell

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med.

Mol. Immunol.

Trends Immunol.

Trends Pharmacol. Sci.

Biochem. Pharmacol.

Stroke

Nature