ToxSci Advance Access originally published online on May 9, 2006
Toxicological Sciences 2006 92(2):507-515; doi:10.1093/toxsci/kfl013
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Low Concentrations of Paraquat Induces Early Activation of Extracellular Signal-Regulated Kinase 1/2, Protein Kinase B, and c-Jun N-terminal Kinase 1/2 Pathways: Role of c-Jun N-Terminal Kinase in Paraquat-Induced Cell Death
* Departamento de Bioquímica y Biología Molecular y Genética, E.U. Enfermería y T.O., Hospital Clínico Veterinario, Departamento de Química Orgánica, and Departamento de Bioquímica y Biología Molecular y Genética, Fac. Veterinaria, E.U. Enfermería y T.O., Universidad de Extremadura, Avda. de la Universidad s/n 10071 Cáceres, Spain
Received March 16, 2006; accepted April 24, 2006
Paraquat is a herbicide with a potential risk to induce parkinsonism due to its demonstrated neurotoxicity and its strong structural similarity to 1-methyl-4-phenylpyridinium (MPP+), a well-known neurotoxin which causes a clinical syndrome similar to Parkinson's disease (PD). However, at present very little is known about the signaling pathways activated by paraquat in any cell system. In this study, we have investigated the effect of paraquat on extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and protein kinase B (PKB) activation in E18 cells. Low concentrations of paraquat stimulated very early increases in ERK1/2, JNK1/2, and PKB phosphorylation. The phosphatidylinositol 3-kinase (PI-3K) inhibitors wortmannin and LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) inhibited early paraquat-induced increases in PKB phosphorylation. Furthermore, early paraquat-mediated increases in ERK1/2 activation were sensitive to the mitogen-activated protein kinase kinase 1 (MEK1) inhibitor PD 98059 (2'-amino-3'-methoxyflavone), whereas JNK1/2 responses were blocked by the JNK1/2 inhibitor SP 600125 (anthra[1-9-cd]pyrazol-6(2H)-one). Pretreatment with wortmannin, LY 294002, or PD 98059 had no effect on paraquat cell death in E18 cells. In contrast, SP 600125 significantly decreased paraquat-induced cell death in E18 cells. In conclusion, we have shown that low concentrations of paraquat stimulate robust very early increases in ERK1/2, JNK1/2, and PKB phosphorylation in E18 cells. Furthermore, the data presented clearly suggest that inhibition of the JNK1/2 pathway protects E18 cells from paraquat-induced cell death and support the fact that inhibition of early activation of JNK1/2 can constitute a potential strategy in PD treatment.
Key Words: paraquat; low concentrations; JNK; cell death; Parkinson.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Gonzalez-Polo, M. Niso-Santano, M. A. Ortiz-Ortiz, A. Gomez-Martin, J. M. Moran, L. Garcia-Rubio, J. Francisco-Morcillo, C. Zaragoza, G. Soler, and J. M. Fuentes Inhibition of Paraquat-Induced Autophagy Accelerates the Apoptotic Cell Death in Neuroblastoma SH-SY5Y Cells Toxicol. Sci., June 1, 2007; 97(2): 448 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Klintworth, K. Newhouse, T. Li, W.-S. Choi, R. Faigle, and Z. Xia Activation of c-Jun N-Terminal Protein Kinase Is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Cell Apoptosis Toxicol. Sci., May 1, 2007; 97(1): 149 - 162. [Abstract] [Full Text] [PDF]
|
|