ToxSci Advance Access published online on May 9, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl013
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1 From Departamento de Bioquímica y Biología Molecular y Genética, E.U. Enfermería y T.O., Universidad de Extremadura, Cáceres, Spain
* To whom correspondence should be addressed. Paraquat is a herbicide with a potential risk to induce parkinsonism due to its demonstrated neurotoxicity and its strong structural similarity to MPP+, a well-known neurotoxin which causes a clinical syndrome similar to PD. However, at present very little is known about the signalling pathways activated by paraquat in any cell system. In this study we have investigated the effect of paraquat on extracellular signal-regulated kinase 1/2 (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 MAPKkinase 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). Pre-treatment 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 supports that inhibition of early activation of JNK1/2 can constitute a potential strategy in PD treatment.
Received March 16, 2006
Accepted March 24, 2006
Neurotoxicology
Low Concentrations of Paraquat Induces Early Activation of ERK 1/2, PKB and JNK1/2 Pathways: Role of JNK in Paraquat-Induced Cell Death
Mireia Niso-Santano 1,
José M. Morán 2,
Lourdes García-Rubio 3,
Ana Gómez-Martín 1,
Rosa A. González-Polo 1,
Germán Soler 4,
and
José M. Fuentes 1 *
2 From Hospital Clínico Veterinario. Universidad de Extremadura, Cáceres, Spain
3 From Departamento de Química Orgánica, Universidad de Extremadura, Cáceres, Spain
4 From Departamento de Bioquímica y Biología Molecular y Genética, Fac. Veterinaria, Universidad de Extremadura, Cáceres, Spain
José M. Fuentes, E-mail: jfuentes{at}unex.es
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