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Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening.

Sun Q, Jia N, Wang W, Jin H, Xu J, Hu H - PLoS ONE (2014)

Bottom Line: The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42.Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment.These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.

ABSTRACT
Mitochondrial dysfunction caused by amyloid β-peptide (Aβ) plays an important role in the pathogenesis of Alzheimer disease (AD). Substantial evidence has indicated that the mitochondrial permeability transition pore (mPTP) opening is involved in Aβ-induced neuronal death and reactive oxygen species (ROS) generation. Astragaloside IV (AS-IV), one of the major active constituents of Astragalus membranaceus, has been reported as an effective anti-oxidant for treating neurodegenerative diseases. However, the molecular mechanisms still need to be clarified. In this study, we investigated whether AS-IV could prevent Aβ1-42-induced neurotoxicity in SK-N-SH cells via inhibiting the mPTP opening. The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42. In addition, pretreatment of AS-IV inhibited the mPTP opening, rescued mitochondrial membrane potential (ΔΨm), enhanced ATP generation, improved the activity of cytochrome c oxidase and blocked cytochrome c release from mitochondria in Aβ1-42 rich milieu. Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment. These data indicate that AS-IV prevents Aβ1-42-induced SK-N-SH cell apoptosis via inhibiting the mPTP opening and ROS generation. These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD.

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AS-IV pretreatment attenuates Aβ1-42-induced SK-N-SH cell death.A. SK-N-SH cells were treated with different concentrations (0–100 µM) of AS-IV for 24 h. B. SK-N-SH cells were treated with different concentrations (0–10 µM) of Aβ1-42 for 24 h. C. SK-N-SH cells were pretreated with different concentrations of AS-IV (10, 25, 50 µM) for 2 h and then incubated with Aβ1-42 (5 µM) for 24 h. Viability of cells was detected by MTT assay. Percentage of cell viability was relative to the untreated vehicle cells. #P<0.01 vs vehicle; *P<0.01 vs Aβ1-42 (n = 3).
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pone-0098866-g002: AS-IV pretreatment attenuates Aβ1-42-induced SK-N-SH cell death.A. SK-N-SH cells were treated with different concentrations (0–100 µM) of AS-IV for 24 h. B. SK-N-SH cells were treated with different concentrations (0–10 µM) of Aβ1-42 for 24 h. C. SK-N-SH cells were pretreated with different concentrations of AS-IV (10, 25, 50 µM) for 2 h and then incubated with Aβ1-42 (5 µM) for 24 h. Viability of cells was detected by MTT assay. Percentage of cell viability was relative to the untreated vehicle cells. #P<0.01 vs vehicle; *P<0.01 vs Aβ1-42 (n = 3).

Mentions: To test the effect of AS-IV, SK-N-SH cells were subjected to various concentrations of AS-IV for 24 h, and no significant difference was observed in cell viability assessed by the MTT assay among the AS-IV (1, 5, 10, 25, 50 µM) group and the vehicle group. However, cells treated with higher dose of AS-IV (100 µM) showed about 10% reduction of cell viability (Fig. 2A, P<0.01). Concentrations of 10, 25, 50 µM of AS-IV were selected to subsequent experiments. To examine the toxicity for oligomer Aβ1-42, SK-N-SH cells were treated with oligomer Aβ1-42 (0.1, 1, 2.5, 5, 10 µM) for 24 h and displayed a dose-dependent reduction in cell viability. Lower concentration of Aβ1-42 (1, 2.5 µM) slightly damaged the cells, and cells were severely impaired by 10 µM Aβ1-42. Application of 5 µM oligomer Aβ1-42 showed a nearly 50% reduction in cell viability and 5 µM Aβ1-42 was selected to be used in the subsequent experiments (Fig. 2B).


Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening.

Sun Q, Jia N, Wang W, Jin H, Xu J, Hu H - PLoS ONE (2014)

AS-IV pretreatment attenuates Aβ1-42-induced SK-N-SH cell death.A. SK-N-SH cells were treated with different concentrations (0–100 µM) of AS-IV for 24 h. B. SK-N-SH cells were treated with different concentrations (0–10 µM) of Aβ1-42 for 24 h. C. SK-N-SH cells were pretreated with different concentrations of AS-IV (10, 25, 50 µM) for 2 h and then incubated with Aβ1-42 (5 µM) for 24 h. Viability of cells was detected by MTT assay. Percentage of cell viability was relative to the untreated vehicle cells. #P<0.01 vs vehicle; *P<0.01 vs Aβ1-42 (n = 3).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4048237&req=5

pone-0098866-g002: AS-IV pretreatment attenuates Aβ1-42-induced SK-N-SH cell death.A. SK-N-SH cells were treated with different concentrations (0–100 µM) of AS-IV for 24 h. B. SK-N-SH cells were treated with different concentrations (0–10 µM) of Aβ1-42 for 24 h. C. SK-N-SH cells were pretreated with different concentrations of AS-IV (10, 25, 50 µM) for 2 h and then incubated with Aβ1-42 (5 µM) for 24 h. Viability of cells was detected by MTT assay. Percentage of cell viability was relative to the untreated vehicle cells. #P<0.01 vs vehicle; *P<0.01 vs Aβ1-42 (n = 3).
Mentions: To test the effect of AS-IV, SK-N-SH cells were subjected to various concentrations of AS-IV for 24 h, and no significant difference was observed in cell viability assessed by the MTT assay among the AS-IV (1, 5, 10, 25, 50 µM) group and the vehicle group. However, cells treated with higher dose of AS-IV (100 µM) showed about 10% reduction of cell viability (Fig. 2A, P<0.01). Concentrations of 10, 25, 50 µM of AS-IV were selected to subsequent experiments. To examine the toxicity for oligomer Aβ1-42, SK-N-SH cells were treated with oligomer Aβ1-42 (0.1, 1, 2.5, 5, 10 µM) for 24 h and displayed a dose-dependent reduction in cell viability. Lower concentration of Aβ1-42 (1, 2.5 µM) slightly damaged the cells, and cells were severely impaired by 10 µM Aβ1-42. Application of 5 µM oligomer Aβ1-42 showed a nearly 50% reduction in cell viability and 5 µM Aβ1-42 was selected to be used in the subsequent experiments (Fig. 2B).

Bottom Line: The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42.Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment.These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.

ABSTRACT
Mitochondrial dysfunction caused by amyloid β-peptide (Aβ) plays an important role in the pathogenesis of Alzheimer disease (AD). Substantial evidence has indicated that the mitochondrial permeability transition pore (mPTP) opening is involved in Aβ-induced neuronal death and reactive oxygen species (ROS) generation. Astragaloside IV (AS-IV), one of the major active constituents of Astragalus membranaceus, has been reported as an effective anti-oxidant for treating neurodegenerative diseases. However, the molecular mechanisms still need to be clarified. In this study, we investigated whether AS-IV could prevent Aβ1-42-induced neurotoxicity in SK-N-SH cells via inhibiting the mPTP opening. The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42. In addition, pretreatment of AS-IV inhibited the mPTP opening, rescued mitochondrial membrane potential (ΔΨm), enhanced ATP generation, improved the activity of cytochrome c oxidase and blocked cytochrome c release from mitochondria in Aβ1-42 rich milieu. Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment. These data indicate that AS-IV prevents Aβ1-42-induced SK-N-SH cell apoptosis via inhibiting the mPTP opening and ROS generation. These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD.

Show MeSH
Related in: MedlinePlus