Posttraumatic administration of luteolin protects mice from traumatic brain injury: Implication of autophagy and inflammation

Xu, Jianguo; Wang, Handong; Lu, Xinyu; Ding, Ke; Zhang, Li; He, Jin; Wei, Wen Jun; Wu, Yong

doi:10.1016/j.brainres.2014.07.042

Cited by 57 publications

(40 citation statements)

References 39 publications

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“…Our data showed that inhibition of autophagy could attenuate fucoxanthin-induced suppression of oxidative stress and apoptosis, suggesting a protective role of autophagy. Consist with these observations showing that autophagy was benefit for TBI1920, our results indicated that autophagy may serve as an additional target for adjuvant anti-oxidative stress and anti-apoptosis therapy.…”

Section: Discussionsupporting

confidence: 73%

Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways

Zhang

Wang

Fan

et al. 2017

Sci Rep

Self Cite

143

149

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Fucoxanthin is abundant in seaweed and is considered as a powerful antioxidant. It has been proposed to possess anti-cancer, anti-obesity and anti-diabetes effects. However, its roles in brain injury models have not been fully understood. The objective of this study was to investigate the neuroprotection of fucoxanthin in models of traumatic brain injury (TBI) and the role of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant-response element (ARE) and Nrf2-autophagy pathways in the putative neuroprotection. We found that fucoxanthin alleviated TBI-induced secondary brain injury, including neurological deficits, cerebral edema, brain lesion and neuronal apoptosis. Moreover, the up-regulation of malondialdehyde (MDA) and the activity of glutathione peroxidase (GPx) were reversed by fucoxanthin treatment. Furthermore, our in vitro studies demonstrated that fucoxanthin increased the neuron survival and reduced the reactive oxygen species (ROS) level. In addition, fucoxanthin activated the Nrf2-ARE pathway and autophagy both in vivo and in vitro, which was proven by the results of immunohistochemistry, western blot and electrophoretic mobility shift assay (EMSA). However, fucoxanthin failed to provide neuroprotection and activated autophagy following TBI in Nrf2−/− mice. In conclusion, our studies indicated that fucoxanthin provided neuroprotective effects in models of TBI, potentially via regulation of the Nrf2-ARE and Nrf2-autophagy pathways.

show abstract

Section: Discussionsupporting

confidence: 73%

Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways

Zhang

Wang

Fan

et al. 2017

Sci Rep

Self Cite

143

149

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“…There are inconsistent reports regarding the effects of luteolin and apigenin on apoptosis and autophagy. Both luteolin and apigenin have been shown as apoptosis and autophagy inducers, which may support their possible chemopreventive or neuroprotective roles [30,61,62]. On the other hand, it was reported that they inhibited apoptosis or autophagy [27,62].…”

Section: Discussionmentioning

confidence: 99%

“…Luteolin attenuates the neurotoxicities induced by peroxide [25], amyloid β (Aβ) protein [26] and 6-OHDA [27–29] in cell culture. In vivo treatment with luteolin protected mice brain from traumatic brain injury by inhibiting inflammatory response and inducing autophagy [30]. Apigenin also protected rat and mice neurons against Aβ-induced neurotoxicity [31,32].…”

Section: Introductionmentioning

confidence: 99%

Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells

Yen

Kou

et al. 2015

PLoS ONE

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Luteolin and apigenin are dietary flavones and exhibit a broad spectrum of biological activities including antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) has been implicated as a causative agent in the development of neurodegenerative disorders. This study investigates the cytoprotective effects of luteolin and apigenin against 4-HNE-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells. Both flavones restored cell viability and repressed caspase-3 and PARP-1 activation in 4-HNE-treated cells. Luteolin also mitigated 4-HNE-mediated LC3 conversion and reactive oxygen species (ROS) production. Luteolin and apigenin up-regulated 4-HNE-mediated unfolded protein response (UPR), leading to an increase in endoplasmic reticulum chaperone GRP78 and decrease in the expression of UPR-targeted pro-apoptotic genes. They also induced the expression of Nrf2-targeted HO-1 and xCT in the absence of 4-HNE, but counteracted their expression in the presence of 4-HNE. Moreover, we found that JNK and p38 MAPK inhibitors significantly antagonized the increase in cell viability induced by luteolin and apigenin. Consistently, enhanced phosphorylation of JNK and p38 MAPK was observed in luteolin- and apigenin-treated cells. In conclusion, this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling, which elicit adaptive cellular stress response pathways, restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity. Luteolin exerts a stronger cytoprotective effect than apigenin possibly due to its higher MAPK, Nrf2 and UPR activation, and ROS scavenging activity.

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“…Most flavonoids have potent antioxidant properties and work to improve redox status; through this, they indirectly reduce neuroinflammation as well. In experimental TBI, luteolin has received the most attention for its ability to reduce a variety of markers of oxidative stress, inhibit apoptosis, reduce inflammation and decrease edema [36,156,212,213]. Interestingly, one study using transgenic Alzheimer mice, demonstrated that luteolin administration prevented TBI-induced upregulation of beta-amyloid, phosphorylated tau and glycogen synthase kinase-3 [156].…”

Section: Flavonoidsmentioning

confidence: 99%

“…Interestingly, one study using transgenic Alzheimer mice, demonstrated that luteolin administration prevented TBI-induced upregulation of beta-amyloid, phosphorylated tau and glycogen synthase kinase-3 [156]. One study suggested that the effects of luteolin are primarily mediated through the Nrf2 pathway [212] and another suggested that increased autophagy may account for other protective effects [213]. Unfortunately, only minimal motor testing has been performed to assess functional recovery using luteolin [36,212], and more will be needed to determine the efficacy of this drug.…”

Section: Flavonoidsmentioning

confidence: 99%

Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies

et al. 2016

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With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens.

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Posttraumatic administration of luteolin protects mice from traumatic brain injury: Implication of autophagy and inflammation

Cited by 57 publications

References 39 publications

Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways

Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways

Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells

Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies

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