Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats.
Lead (Pb(2+)) is widely recognized as a neurotoxicant whose mechanisms of action are not completely established. We have previously demonstrated that Pb(2+) can activate the p38(MAPK) pathway and increase the phosphorylation of Hsp27 in bovine adrenal chromaffin cells and human SH SY5Y cells over a short incubation period (1 h). In the present work we analyzed the effects of Pb(2+) administered in vivo on the level and the phosphorylation state of ERK1/2 and p38(MAPK) in the hippocampus of immature rats. Rats were treated with lead acetate (2, 8 or 12 mg/kg, i.p.) or saline (control) over the 8th to 12th postnatal days, and hippocampal slices were prepared on the 14th day. The Pb(2+) level in the lead-treated animals increased 2.5-6-fold in the blood (3.0-6.0 microg/dl) and 2.0-3.0-fold in the forebrain (78-103 ng/g wet weight), compared to control (saline). The phosphorylation of both ERK1/2 and p38(MAPK) was significantly increased by prior exposure to Pb(2+) in vivo. In in vitro experiments, hippocampal slices from 14-day-old rats were exposed to Pb(2+) (1-10 microM) for 1 and 3 h. There were no changes in the phosphorylation state of ERK and p38(MAPK) for 1-h incubation, whereas a significant increase of ERK1/2 and p38(MAPK) phosphorylation by Pb(2+) (5 microM) was observed for the 3-h incubation. Cell viability measured using MTT was not modified in any of the conditions tested. These results indicate that the phosphorylation of hippocampal ERK1/2 and p38(MAPK) is stimulated by lead in a period of rapid brain development, an effect that may underlie, at least in part, the neurotoxicty elicited by this metal.
Cordova
Fabiano M
FM
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, SC, 88040-900, Florianópolis, Brazil.
Rodrigues
Ana Lúcia S
AL
Giacomelli
Maria B O
MB
Oliveira
Camila S
CS
Posser
Thaís
T
Dunkley
Peter R
PR
Leal
Rodrigo B
RB
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007854:Lead / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D020714:Maximum Tolerated Dose; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
D007854:Lead; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases