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Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells.
Toxicol Lett. 2011 Apr 25; 202(2):133-41.TL

Abstract

Fipronil (FPN) is a phenylpyrazole insecticide acted on insect gamma-aminobutyric acid (GABA) receptors. Although action of FPN is restricted on insect neuronal or muscular transmitter system, a few studies have assessed the effects of this neurotoxicant on neuronal cell death. To determine the mechanisms underlying FPN-induced neuronal cell death, we investigated whether reactive oxygen species (ROS) plays a role in FPN-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. FPN was cytotoxic to these cells and its cytotoxicity showed a concentration-dependent manner. Additionally, FPN treatment significantly decreased the tyrosine hydroxylase (TH) expression without change of glutamic acid decarboxylase 65 (GAD65) expression. FPN-induced dopaminergic cell death involved in increase of ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FPN treatment, dopamine (DA) levels decreased significantly in both cell and culture media, and oxidative effects of DA were blocked by NAC pretreatment. We showed that cell death in response to FPN was due to apoptosis since FPN increased cytochrome c release into the cytosol and activated caspase-3. It also led to nuclear accumulation of p53 and reduced the level of Bcl-2 protein in a concentration-dependent manner. Additionally, FPN altered the level of Akt/glycogen synthase kinase-3 (GSK3β) phosphorylation. FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3β on Ser9 which inactivates GSK3β, decreased after treatment with FPN. Furthermore, inhibition of the GSK3β signal protected the cell against FPN-induced cell death. These results suggest that regulation of GSK3β activity may control the apoptosis induced by FPN-induced oxidative stress associated with neuronal cell death.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, Hanyang University, 133-791 Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21296133

Citation

Lee, Jeong Eun, et al. "Akt/GSK3β Signaling Is Involved in Fipronil-induced Apoptotic Cell Death of Human Neuroblastoma SH-SY5Y Cells." Toxicology Letters, vol. 202, no. 2, 2011, pp. 133-41.
Lee JE, Kang JS, Ki YW, et al. Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells. Toxicol Lett. 2011;202(2):133-41.
Lee, J. E., Kang, J. S., Ki, Y. W., Lee, S. H., Lee, S. J., Lee, K. S., & Koh, H. C. (2011). Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells. Toxicology Letters, 202(2), 133-41. https://doi.org/10.1016/j.toxlet.2011.01.030
Lee JE, et al. Akt/GSK3β Signaling Is Involved in Fipronil-induced Apoptotic Cell Death of Human Neuroblastoma SH-SY5Y Cells. Toxicol Lett. 2011 Apr 25;202(2):133-41. PubMed PMID: 21296133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells. AU - Lee,Jeong Eun, AU - Kang,Jin Sun, AU - Ki,Yeo-Woon, AU - Lee,Sang-Hun, AU - Lee,Soo-Jin, AU - Lee,Kyung Suk, AU - Koh,Hyun Chul, Y1 - 2011/02/04/ PY - 2010/11/23/received PY - 2011/01/27/revised PY - 2011/01/31/accepted PY - 2011/2/8/entrez PY - 2011/2/8/pubmed PY - 2011/6/4/medline SP - 133 EP - 41 JF - Toxicology letters JO - Toxicol Lett VL - 202 IS - 2 N2 - Fipronil (FPN) is a phenylpyrazole insecticide acted on insect gamma-aminobutyric acid (GABA) receptors. Although action of FPN is restricted on insect neuronal or muscular transmitter system, a few studies have assessed the effects of this neurotoxicant on neuronal cell death. To determine the mechanisms underlying FPN-induced neuronal cell death, we investigated whether reactive oxygen species (ROS) plays a role in FPN-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. FPN was cytotoxic to these cells and its cytotoxicity showed a concentration-dependent manner. Additionally, FPN treatment significantly decreased the tyrosine hydroxylase (TH) expression without change of glutamic acid decarboxylase 65 (GAD65) expression. FPN-induced dopaminergic cell death involved in increase of ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FPN treatment, dopamine (DA) levels decreased significantly in both cell and culture media, and oxidative effects of DA were blocked by NAC pretreatment. We showed that cell death in response to FPN was due to apoptosis since FPN increased cytochrome c release into the cytosol and activated caspase-3. It also led to nuclear accumulation of p53 and reduced the level of Bcl-2 protein in a concentration-dependent manner. Additionally, FPN altered the level of Akt/glycogen synthase kinase-3 (GSK3β) phosphorylation. FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3β on Ser9 which inactivates GSK3β, decreased after treatment with FPN. Furthermore, inhibition of the GSK3β signal protected the cell against FPN-induced cell death. These results suggest that regulation of GSK3β activity may control the apoptosis induced by FPN-induced oxidative stress associated with neuronal cell death. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/21296133/Akt/GSK3β_signaling_is_involved_in_fipronil_induced_apoptotic_cell_death_of_human_neuroblastoma_SH_SY5Y_cells_ L2 - http://www.diseaseinfosearch.org/result/5160 DB - PRIME DP - Unbound Medicine ER -