Astaxanthin Activates Nuclear Factor Erythroid-Related  Factor 2 and the Antioxidant Responsive Element (Nrf2-ARE) Pathway in the Brain after Subarachnoid Hemorrhage in Rats and Attenuates Early Brain Injury

Wu, Qi; Zhang, Xiangsheng; Handong, Wang; Zhang, Xin; Yu, Qing; Li, Wei; Zhou, Meifang; Wang, Xiaoliang

doi:10.3390/md12126125

Cited by 131 publications

(93 citation statements)

References 37 publications

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“…) and astaxanthin (Wu et al . ) in protecting the retina and other tissues from oxidative stress and cytotoxic injury through the activation of Nrf2. We have shown that RS9 and BARD, which are known Nrf2 activators, have in vivo and in vitro protective effects against oxidative injury in brain ischemia and hemorrhagic transformation under warfarin anticoagulation (Takagi et al .…”

Section: Discussionmentioning

confidence: 99%

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Inoue

Shimazawa

Noda

et al. 2017

Journal of Neurochemistry

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The retina is highly sensitive to oxidative stress because of its high consumption of oxygen associated with the phototransductional processes. Recent findings have suggested that oxidative stress is involved in the pathology of age-related macular degeneration, a progressive degeneration of the central retina. A well-known environmental risk factor is light exposure, as excessive and continuous light exposure can damage photoreceptors. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that controls antioxidative responses and phase 2 enzymes. Thus, we hypothesized that RS9, a specific activator of Nrf2, decreases light-induced retinal cell death in vivo and in vitro. Nrf2 was detected in the nucleus of the 661W cells exposed to RS9 and also after light exposure, and the Nrf2-antioxidant response element binding was increased in 661W cells after exposure to RS9. Consequentially, the expression of the phase 2 enzyme's mRNAs of Ho-1, Nqo-1, and Gclm genes was increased in 661W cells after exposure to RS9. Furthermore, RS9 decreased the light-induced death of 661W cells (2500 lux, 24 h), and also reduced the functional damages and the histological degeneration of the nuclei in the outer nuclear layer or the retina in the in vivo studies (8000 lux, 3 h). Heme oxygenase-1 was increased after light exposure, and Nrf2 was translocated into the nucleus after light exposure in vivo. Silencing of Ho-1 reduced the protective effects of RS9 against light-induced death of 661W cells. These findings indicate that RS9 has therapeutic potential for retinal diseases that are aggravated by light exposure.

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Section: Discussionmentioning

confidence: 99%

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Inoue

Shimazawa

Noda

et al. 2017

Journal of Neurochemistry

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“…Following insults like hypoxia-ischemic or SAH, the production of reactive oxygen species (ROS) exceeds the ability of the endogenous anti-oxidant system, leading to oxidative stress and cell death (Wu et al, 2014; Zhang et al, 2016). Excessive production of ROS results in protein breakdown, lipid peroxidation, and DNA damage, leading to neuronal damage, BBB disruption, cellular apoptosis, and endothelial injury (Ayer and Zhang, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Nrf2 has been shown to be an important antioxidant protection in various CNS diseases, including SAH (Chen et al, 2011; Wu et al, 2014), traumatic brain injury (Jin et al, 2008), and neurodegenerative disorders (van Muiswinkel and Kuiperij, 2005). Under the pathological conditions, such as ROS, Nrf2 rapidly translocates from the cytoplasm to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of a Smoothened Receptor Agonist against Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats

Hu¹,

Wang

et al. 2017

Front. Cell. Neurosci.

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The sonic hedgehog (Shh) signaling pathway plays a fundamental role in the central nervous system (CNS) development, but its effects on neural cell survival and brain repair after subarachnoid hemorrhage (SAH) has not been well-investigated. The present study was undertaken to evaluate the influence of an agonist of the Shh co-receptor Smoothened (Smo), purmorphamine (PUR), on early brain injury (EBI) as well as the underlying mechanisms after SAH. PUR was administered via an intraperitoneal injection with a dose of 0.5, 1, and 5 mg/kg at 2, 6, 24, and 46 h after SAH in rat model. The results showed that PUR treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex (PFC), associated with a decrease in Bax/Bcl-2 ratio and suppression of caspase-3 activation at 48 h after SAH. PUR also promoted phospho-ERK levels. Additionally, PUR treatment markedly decreased MDA concentration accompanied with the elevation in the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in PFC. Notably, PUR treatment significantly reversed the changes of Shh pathway mediators containing Patched, Gli1, and Shh by SAH insult, and the neuroprotection of PUR on SAH was blocked by Smo antagonist cyclopamine. These results indicated that PUR exerts neuroprotection against SAH-evoked injury in rats, mediated in part by anti-apoptotic and anti-oxidant mechanism, up-regulating phospho-ERK levels, mediating Shh signaling molecules in the PFC.

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“…HO-1 is one of the important genes in the brain and is activated by Nrf2, as demonstrated by intensive studies that have a crucial role in providing shelter to neurons against cell death. Accordingly, numerous reports have described that Nrf2 activation [40, 41] induces an increase in HO-1 in response to several neurodegenerative disorders [42]. Many studies have shown that HO-1 activation is an important response to the threat of oxidative stress to neurons as it can rescue neurons from oxidative stress and cell death [43, 44].…”

Section: Discussionmentioning

confidence: 99%

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain

Shah

Amin

Khan

et al. 2016

J Neuroinflammation

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BackgroundGlutamate-induced excitotoxicity, oxidative damage, and neuroinflammation are believed to play an important role in the development of a number of CNS disorders. We recently reported that a high dose of glutamate could induce AMPK-mediated neurodegeneration in the postnatal day 7 (PND7) rat brain. Yet, the mechanism of glutamate-induced oxidative stress and neuroinflammation in the postnatal brain is not well understood. Here, we report for the first time the mechanism of glutamate-induced oxidative damage, neuroinflammation, and neuroprotection by polyphenolic anthocyanins in PND7.MethodsPND7 rat brains, SH-SY5Y, and BV2 cells treated either alone with glutamate or in combination with anthocyanins and compound C were examined with Western blot and immunofluorescence techniques. Additionally, reactive oxygen species (ROS) assay and other ELISA kit assays were employed to know the therapeutic efficacy of anthocyanins against glutamate.ResultsA single injection of glutamate to developing rats significantly increased brain glutamate levels, activated and phosphorylated AMPK induction, and inhibited nuclear factor-E2-related factor 2 (Nrf2) after 2, 3, and 4 h in a time-dependent manner. In contrast, anthocyanin co-treatment significantly reduced glutamate-induced AMPK induction, ROS production, neuroinflammation, and neurodegeneration in the developing rat brain. Most importantly, anthocyanins increased glutathione (GSH and GSSG) levels and stimulated the endogenous antioxidant system, including Nrf2 and heme oxygenase-1 (HO-1), against glutamate-induced oxidative stress. Interestingly, blocking AMPK with compound C in young rats abolished glutamate-induced neurotoxicity. Similarly, all these experiments were replicated in SH-SY5Y cells by silencing AMPK with siRNA, which suggests that AMPK is the key mediator in glutamate-induced neurotoxicity.ConclusionsHere, we report for the first time that anthocyanins can potentially decrease glutamate-induced neurotoxicity in young rats. Our work demonstrates that glutamate is toxic to the developing rat brain and that anthocyanins can minimize the severity of glutamate-induced neurotoxicity in an AMPK-dependent manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0752-y) contains supplementary material, which is available to authorized users.

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Astaxanthin Activates Nuclear Factor Erythroid-Related Factor 2 and the Antioxidant Responsive Element (Nrf2-ARE) Pathway in the Brain after Subarachnoid Hemorrhage in Rats and Attenuates Early Brain Injury

Cited by 131 publications

References 37 publications

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

Neuroprotective Effects of a Smoothened Receptor Agonist against Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats

Anthocyanins abrogate glutamate-induced AMPK activation, oxidative stress, neuroinflammation, and neurodegeneration in postnatal rat brain

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