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Phlorofucofuroeckol Improves Glutamate-Induced Neurotoxicity through Modulation of Oxidative Stress-Mediated Mitochondrial Dysfunction in PC12 Cells

View Article: PubMed Central - PubMed

ABSTRACT

Stroke is a complex neurodegenerative disorder with a clinically high prevalence and mortality. Despite many efforts to protect against ischemic stroke, its incidence and related permanent disabilities continue to increase. In this study, we found that pretreatment with phlorofucofuroeckol (PFF), isolated from brown algae species, significantly increased cell viability in glutamate-stimulated PC12 cells. Additionally, glutamate-stimulated cells showed irregular morphology, but PFF pretreatment resulted in improved cell morphology, which resembled that in cells cultured under normal conditions. We further showed that PFF pretreatment effectively inhibited glutamate-induced apoptotic cell death in a caspase-dependent manner. Reactive oxygen species (ROS) induced by oxidative stress are closely associated with ischemia-induced neurological diseases. Exposure of PC12 cells to glutamate induced abundant production of intracellular ROS and mitochondrial dysfunction, which was attenuated by PFF in a dose-dependent manner. In vivo studies revealed that PFF-mediated prevention was achieved predominantly through inhibition of apoptosis and mitochondrial ROS generation. Taken together, these results suggest the possibility of PFF as a neuroprotective agent in ischemic stroke.

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Related in: MedlinePlus

A schematic model depicting the neuroprotective roles of PFF in an ischemic stroke model.Glutamate caused disturbances in the oxidant/antioxidant balance in the cellular system and then resulted in a permeability transition of the mitochondrial membrane. This further altered the translocation of the mitochondrial death-signaling pro/anti-apoptotic proteins, such as Bax, Bcl-2, and cytochrome c, resulting in the activation of the caspase cascade and DNA damage, culminating in cell death. Administration of PFF helped to maintain the oxidant/antioxidant balance and alter the changes in the mitochondria-mediated apoptotic signaling cascade that resulted in neuronal cell damage.
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pone.0163433.g007: A schematic model depicting the neuroprotective roles of PFF in an ischemic stroke model.Glutamate caused disturbances in the oxidant/antioxidant balance in the cellular system and then resulted in a permeability transition of the mitochondrial membrane. This further altered the translocation of the mitochondrial death-signaling pro/anti-apoptotic proteins, such as Bax, Bcl-2, and cytochrome c, resulting in the activation of the caspase cascade and DNA damage, culminating in cell death. Administration of PFF helped to maintain the oxidant/antioxidant balance and alter the changes in the mitochondria-mediated apoptotic signaling cascade that resulted in neuronal cell damage.

Mentions: Bioactive derivatives isolated from Ecklonia species have shown multifunctional properties, including anti-cancer, anti-inflammatory, and anti-diabetic effects [15]. For example, dieckol isolated from Ecklonia cava, one of the phlorotannin polyphenol compounds, regulated oxidative stress and apoptosis to protect against the glucotoxicity of hyperglycemia [58]. Dieckol also resulted in suppression of ovarian tumor cells through the activation of caspase-dependent apoptosis [59]. Additionally, PFF-A isolated from Ecklonia stolonifera exhibited cytoprotective effects through inhibition of caspase-dependent apoptosis in tacrine-treated HepG2 cells [60]. Our results indicated that glutamate-stimulated PC12 cells showed increased apoptosis, DNA fragmentation, and caspase activation. However, PFF significantly inhibited glutamate-induced upregulation of these effects (Fig 3). These data suggest that PFF increases neuronal cell survival through inhibition of both early and late apoptosis, as well as regulation of ROS generation. Our proposed model for the protective pathway of PFF is summarized in Fig 7.


Phlorofucofuroeckol Improves Glutamate-Induced Neurotoxicity through Modulation of Oxidative Stress-Mediated Mitochondrial Dysfunction in PC12 Cells
A schematic model depicting the neuroprotective roles of PFF in an ischemic stroke model.Glutamate caused disturbances in the oxidant/antioxidant balance in the cellular system and then resulted in a permeability transition of the mitochondrial membrane. This further altered the translocation of the mitochondrial death-signaling pro/anti-apoptotic proteins, such as Bax, Bcl-2, and cytochrome c, resulting in the activation of the caspase cascade and DNA damage, culminating in cell death. Administration of PFF helped to maintain the oxidant/antioxidant balance and alter the changes in the mitochondria-mediated apoptotic signaling cascade that resulted in neuronal cell damage.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036853&req=5

pone.0163433.g007: A schematic model depicting the neuroprotective roles of PFF in an ischemic stroke model.Glutamate caused disturbances in the oxidant/antioxidant balance in the cellular system and then resulted in a permeability transition of the mitochondrial membrane. This further altered the translocation of the mitochondrial death-signaling pro/anti-apoptotic proteins, such as Bax, Bcl-2, and cytochrome c, resulting in the activation of the caspase cascade and DNA damage, culminating in cell death. Administration of PFF helped to maintain the oxidant/antioxidant balance and alter the changes in the mitochondria-mediated apoptotic signaling cascade that resulted in neuronal cell damage.
Mentions: Bioactive derivatives isolated from Ecklonia species have shown multifunctional properties, including anti-cancer, anti-inflammatory, and anti-diabetic effects [15]. For example, dieckol isolated from Ecklonia cava, one of the phlorotannin polyphenol compounds, regulated oxidative stress and apoptosis to protect against the glucotoxicity of hyperglycemia [58]. Dieckol also resulted in suppression of ovarian tumor cells through the activation of caspase-dependent apoptosis [59]. Additionally, PFF-A isolated from Ecklonia stolonifera exhibited cytoprotective effects through inhibition of caspase-dependent apoptosis in tacrine-treated HepG2 cells [60]. Our results indicated that glutamate-stimulated PC12 cells showed increased apoptosis, DNA fragmentation, and caspase activation. However, PFF significantly inhibited glutamate-induced upregulation of these effects (Fig 3). These data suggest that PFF increases neuronal cell survival through inhibition of both early and late apoptosis, as well as regulation of ROS generation. Our proposed model for the protective pathway of PFF is summarized in Fig 7.

View Article: PubMed Central - PubMed

ABSTRACT

Stroke is a complex neurodegenerative disorder with a clinically high prevalence and mortality. Despite many efforts to protect against ischemic stroke, its incidence and related permanent disabilities continue to increase. In this study, we found that pretreatment with phlorofucofuroeckol (PFF), isolated from brown algae species, significantly increased cell viability in glutamate-stimulated PC12 cells. Additionally, glutamate-stimulated cells showed irregular morphology, but PFF pretreatment resulted in improved cell morphology, which resembled that in cells cultured under normal conditions. We further showed that PFF pretreatment effectively inhibited glutamate-induced apoptotic cell death in a caspase-dependent manner. Reactive oxygen species (ROS) induced by oxidative stress are closely associated with ischemia-induced neurological diseases. Exposure of PC12 cells to glutamate induced abundant production of intracellular ROS and mitochondrial dysfunction, which was attenuated by PFF in a dose-dependent manner. In vivo studies revealed that PFF-mediated prevention was achieved predominantly through inhibition of apoptosis and mitochondrial ROS generation. Taken together, these results suggest the possibility of PFF as a neuroprotective agent in ischemic stroke.

No MeSH data available.


Related in: MedlinePlus