Curcumin protects against methylmercury-induced cytotoxicity in primary rat astrocytes by activating the Nrf2/ARE pathway independently of PKCδ

Bobo Yang, Changsheng Yin, Yun Zhou, Qiang Wang, Yuanyue Jiang, Yu Bai, Hai Qian, Guangwei Xing, Suhua Wang, Fang Li, Yun Feng, Yubin Zhang, Jiyang Cai, Michael Aschner, Rongzhu Lu

Research output: Contribution to journalArticle

Abstract

Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31–8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.

Original languageEnglish (US)
Article number152248
JournalToxicology
Volume425
DOIs
StatePublished - Sep 1 2019

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Antioxidant Response Elements
Curcumin
Cytotoxicity
Astrocytes
Protein Kinase C
Rats
Protein C Inhibitor
Cell death
Protein Kinase Inhibitors
Cell Death
NAD(P)H Dehydrogenase (Quinone)
Curcuma
Rhizome
Heme Oxygenase-1
Oxidative stress
Cytoprotection
Polyphenols
NADP
L-Lactate Dehydrogenase
Catalase

Keywords

  • Astrocytes
  • Curcumin
  • Methylmercury
  • Nrf2
  • PKCδ

ASJC Scopus subject areas

  • Toxicology

Cite this

Curcumin protects against methylmercury-induced cytotoxicity in primary rat astrocytes by activating the Nrf2/ARE pathway independently of PKCδ. / Yang, Bobo; Yin, Changsheng; Zhou, Yun; Wang, Qiang; Jiang, Yuanyue; Bai, Yu; Qian, Hai; Xing, Guangwei; Wang, Suhua; Li, Fang; Feng, Yun; Zhang, Yubin; Cai, Jiyang; Aschner, Michael; Lu, Rongzhu.

In: Toxicology, Vol. 425, 152248, 01.09.2019.

Research output: Contribution to journalArticle

Yang, B, Yin, C, Zhou, Y, Wang, Q, Jiang, Y, Bai, Y, Qian, H, Xing, G, Wang, S, Li, F, Feng, Y, Zhang, Y, Cai, J, Aschner, M & Lu, R 2019, 'Curcumin protects against methylmercury-induced cytotoxicity in primary rat astrocytes by activating the Nrf2/ARE pathway independently of PKCδ', Toxicology, vol. 425, 152248. https://doi.org/10.1016/j.tox.2019.152248
Yang, Bobo ; Yin, Changsheng ; Zhou, Yun ; Wang, Qiang ; Jiang, Yuanyue ; Bai, Yu ; Qian, Hai ; Xing, Guangwei ; Wang, Suhua ; Li, Fang ; Feng, Yun ; Zhang, Yubin ; Cai, Jiyang ; Aschner, Michael ; Lu, Rongzhu. / Curcumin protects against methylmercury-induced cytotoxicity in primary rat astrocytes by activating the Nrf2/ARE pathway independently of PKCδ. In: Toxicology. 2019 ; Vol. 425.
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abstract = "Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31–8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.",
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AU - Yang, Bobo

AU - Yin, Changsheng

AU - Zhou, Yun

AU - Wang, Qiang

AU - Jiang, Yuanyue

AU - Bai, Yu

AU - Qian, Hai

AU - Xing, Guangwei

AU - Wang, Suhua

AU - Li, Fang

AU - Feng, Yun

AU - Zhang, Yubin

AU - Cai, Jiyang

AU - Aschner, Michael

AU - Lu, Rongzhu

PY - 2019/9/1

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N2 - Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31–8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.

AB - Methylmercury (MeHg) is a ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. Curcumin, a polyphenol obtained from the rhizome of turmeric, has well-known antioxidant functions. Here, we evaluated curcumin's efficacy in mitigating MeHg-induced cytotoxicity and further investigated the underlying mechanism of this neuroprotection in primary rat astrocytes. Pretreatment with curcumin (2, 5, 10 and 20 μM for 3, 6, 12 or 24 h) protected against MeHg-induced (5 μM for 6 h) cell death in a time and dose-dependent manner. Curcumin (2, 5, 10 or 20 μM) pretreatment for 12 h significantly ameliorated the MeHg-induced astrocyte injury and oxidative stress, as evidenced by morphological alterations, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, and glutathione (GSH) and catalase (CAT) levels. Moreover, curcumin pretreatment increased Nrf2 nuclear translocation and downstream enzyme expression, heme oxygenase-1 (HO-1) and NADPH quinone reductase-1 (NQO1). Knockdown of Nrf2 with siRNA attenuated the protective effect of curcumin against MeHg-induced cell death. However, both the pan-protein kinase C (PKC) inhibitor, Ro 31–8220, and the selective PKCδ inhibitor, rottlerin, failed to suppress the curcumin-activated Nrf2/Antioxidant Response Element(ARE) pathway and attenuate the protection exerted by curcumin. Taken together, these findings confirm that curcumin protects against MeHg-induced neurotoxicity by activating the Nrf2/ARE pathway and this protection is independent of PKCδ activation. More studies are needed to understand the mechanisms of curcumin cytoprotection.

KW - Astrocytes

KW - Curcumin

KW - Methylmercury

KW - Nrf2

KW - PKCδ

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