Astaxanthin Protects PC12 Cells against Homocysteine- and Glutamate-Induced Neurotoxicity

Chang, Chi Huang; Chen, Kuan Chou; Liaw, Kuo Chun; Peng, Chiung Chi; Peng, Robert Y.

doi:10.3390/molecules25010214

Cited by 16 publications

(9 citation statements)

References 64 publications

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“…Correspondingly, we also found significant loss in neuronal survivability on glutamate addition. Interestingly, similar to the earlier observations [ 36 , 46 ], we observed high neuronal survivability upon glutamate exposure in AST preincubated cultures. In neurons, the glutamate toxicity is majorly due to the excessive intracellular calcium overload, which involves a rapid primary calcium influx and an irreversible SSCR [ 18 , 47 ].…”

Section: Discussionsupporting

confidence: 92%

“…The SSCR is associate with the loss of mitochondrial function, which in turn depends on the primary influx of calcium into the neuron from the extracellular space [ 6 ]. Earlier reports by fluorometric analysis have suggested that AST attenuates the [Ca 2+ ]i response in PC12 and SH-SY5Y cells upon glutamate application [ 36 , 46 ], and in hippocampal neurons upon NMDA application [ 27 , 37 ]. However, these studies have not demonstrated AST-mediated inhibition of both the primary Ca 2+ influx as well as the SSCR upon ionotropic glutamate receptor agonists activation.…”

Section: Discussionmentioning

confidence: 99%

“…This result corroborates with the report of AST inhibition of mitochondrial H 2 O 2 upon Aβ toxicity in hippocampal neurons [ 27 ], as well as with the suppressing ROS formation in the rat model of transient cerebral ischemia [ 58 ]. Additionally, reports have suggested that AST inhibits the glutamate-mediated increase in ROS in SH-SY5Y and PC12 cells [ 36 , 46 ]. Interestingly, our results demonstrate that AST could inhibit both Ψm and [Ca 2+ ]m accumulation during excitotoxicity, which were not performed by others.…”

Section: Discussionmentioning

confidence: 99%

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Astaxanthin Protection against Neuronal Excitotoxicity via Glutamate Receptor Inhibition and Improvement of Mitochondrial Function

et al. 2022

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Excitotoxicity is known to associate with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, as well as aging, stroke, trauma, ischemia and epilepsy. Excessive release of glutamate, overactivation of glutamate receptors, calcium overload, mitochondrial dysfunction and excessive reactive oxygen species (ROS) formation are a few of the suggested key mechanisms. Astaxanthin (AST), a carotenoid, is known to act as an antioxidant and protect neurons from excitotoxic injuries. However, the exact molecular mechanism of AST neuroprotection is not clear. Thus, in this study, we investigated the role of AST in neuroprotection in excitotoxicity. We utilized primary cortical neuronal culture and live cell fluorescence imaging for the study. Our results suggest that AST prevents neuronal death, reduces ROS formation and decreases the abnormal mitochondrial membrane depolarization induced by excitotoxic glutamate insult. Additionally, AST modulates intracellular calcium levels by inhibiting peak and irreversible secondary sustained calcium levels in neurons. Furthermore, AST regulates the ionotropic glutamate subtype receptors NMDA, AMPA, KA and mitochondrial calcium. Moreover, AST decreases NMDA and AMPA receptor protein expression levels, while KA remains unaffected. Overall, our results indicate that AST protects neurons from excitotoxic neuronal injury by regulating ionotropic glutamate receptors, cytosolic secondary calcium rise and mitochondrial calcium buffering. Hence, AST could be a promising therapeutic agent against excitotoxic insults in neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Astaxanthin Protection against Neuronal Excitotoxicity via Glutamate Receptor Inhibition and Improvement of Mitochondrial Function

et al. 2022

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“…These responses were explained by Chang et al. (2020), who suggested that glutamate provokes a significant amount of ROS production. ROS induces inflammation and causes the release of multiple pro‐inflammatory cytokines, including TNF‐α and IL‐6, which play a role in the inflammatory hepatic response and therefore cause liver injury (Bryan et al., 2012).…”

Section: Discussionmentioning

confidence: 91%

Anti‐inflammatory activity of ginger modulates macrophage activation against the inflammatory pathway of monosodium glutamate

et al. 2021

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Monosodium glutamate (MSG) has been traditionally used as a flavor enhancer and is added to many foods. The chronic consumption of MSG has been suggested as causing toxicity, inflammation, obesity, type 2 diabetes, and pre‐malignant changes. The use of medicinal plants and their products, such as ginger, against the effects of MSG has been suggested to have a protective effect. To evaluate the anti‐inflammatory activity of ginger against the effects of MSG, we conducted a serial inflammatory analysis of MSG‐ and ginger‐treated rats, focusing particularly on liver pathology. The consumption of ginger as an unconventional therapy against the effects of MSG resulted in significant anti‐inflammatory activity. We found that it was possible to diagnose MSG‐associated inflammatory pathogenesis using inflammatory mediators. Ginger consumption produced protective effects on health, minimized adverse effects, and may be applicable for food development and the treatment of many inflammatory diseases. Practical applications The chronic administration of monosodium glutamate (MSG) as a flavor enhancer has been suggested to produce toxicity, inflammation, and pre‐malignant changes in organs. Ginger has protective effects, with potent anti‐inflammatory and anti‐fibrotic activity against MSG administration. This study is the first to report that ginger modulated the inflammatory and fibrotic effects of MSG and improved immunological indices reflecting the involvement of inflammatory and fibrotic markers and polysaccharide content in the activation of macrophages. These findings support the further use of ginger as a supplement for food enhancement and as an anti‐fibrotic, anti‐inflammatory, and therapeutic agent in pharmaceutical therapies against autoimmune and inflammatory diseases, such as rheumatoid arthritis, lupus, and ulcerative colitis, as well as MSG‐associated inflammatory diseases.

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“…A remarkable property of ASX is that, unlike many other natural antioxidants, it readily crosses the blood-brain barrier; due to this property, ASX has been used successfully in rodents to reverse both ischemia-reperfusion-induced brain damage [5] and cognitive impairment [6,7]. In neuron-like HT22 cells [7], PC12 cells [8] or SH-SY5Y cells [9][10][11] ASX suppresses the excitotoxic responses induced by glutamate, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) or acetaldehyde. Although the neuroprotective effects of ASX might involve decreasing oxidative stress and improving mitochondrial integrity [12], whether ASX induces adaptive responses such as changes in redox-sensitive cellular signaling processes-including calcium (Ca 2+ )-dependent signaling pathways and reactive oxygen species (ROS) generation remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation

et al. 2020

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Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca2+ concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca2+ dysregulation. Here, we studied whether ASX protects neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, a noxious process which decreases cellular viability, alters gene expression and promotes excessive mROS production. Incubation of the neuronal cell line SH-SY5Y with NMDA decreased cellular viability and increased mitochondrial superoxide production; pre-incubation with ASX prevented these effects. Additionally, incubation of SH-SY5Y cells with ASX effectively reduced the basal mROS production and prevented hydrogen peroxide-induced cell death. In primary hippocampal neurons, transfected with a genetically encoded cytoplasmic Ca2+ sensor, ASX also prevented the increase in intracellular Ca2+ concentration induced by NMDA. We suggest that, by preventing the noxious mROS and Ca2+ increases that occur under excitotoxic conditions, ASX could be useful as a therapeutic agent in neurodegenerative pathologies that involve alterations in Ca2+ homeostasis and ROS generation.

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Astaxanthin Protects PC12 Cells against Homocysteine- and Glutamate-Induced Neurotoxicity

Cited by 16 publications

References 64 publications

Astaxanthin Protection against Neuronal Excitotoxicity via Glutamate Receptor Inhibition and Improvement of Mitochondrial Function

Astaxanthin Protection against Neuronal Excitotoxicity via Glutamate Receptor Inhibition and Improvement of Mitochondrial Function

Anti‐inflammatory activity of ginger modulates macrophage activation against the inflammatory pathway of monosodium glutamate

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation

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