Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK.
The developing brain is very sensitive to damage by toxic agents, many of which only manifest in adulthood. Cadmium [Cd(II)] is an environmental pollutant which is widely used in industry and is a constituent of tobacco smoke. Exposure to Cd(II) has been linked to detrimental effects on mammalian cells including neural cells. We have investigated the action of Cd(II) on immature hippocampus by assessing cell viability and modulation of AKT/PKB and mitogen-activated protein kinase (MAPK) family members including extracellular signal-regulated kinase (ERK)-1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). Hippocampal slices from immature rats (postnatal day 14; PN14) were incubated with Cd(II) (5-200 microM) for 3h and the effects on protein phosphorylation were analyzed by western blotting. Phosphorylation of p38(MAPK) was enhanced by Cd(II) at all doses tested. Cd(II) also stimulated the phosphorylation of ERK1/2 in a concentration-dependent manner. However, the phosphorylation of JNK and AKT was not altered by the metal. Moreover, Cd(II) reduced cell viability, as measured by MTT reduction. Inhibition of p38 MAPK by SB203580 aggravated the acute Cd(II)-induced impairment of cell viability, whereas inhibition of MEK by PD98059 did not alter the effects of Cd(II). The present data suggest that in immature hippocampal cells p38 MAPK may be a part of signaling pathway that counteracts acute Cd(II) neurotoxicity. In conclusion, our results showed that Cd(II) impairs cell viability and disturbs MAPKs pathways in an important developmental stage for synaptic organization.
Rigon
Ana Paula
AP
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Cordova
Fabiano M
FM
Oliveira
Camila S
CS
Posser
Thaís
T
Costa
Ana Paula
AP
Silva
Ilza G
IG
Santos
Daiane A
DA
Rossi
Francesco M
FM
Rocha
João Batista T
JB
Leal
Rodrigo B
RB
D000818:Animals; D000831:Animals, Newborn; D002104:Cadmium / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009498:Neurotoxins / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009498:Neurotoxins; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; D002104:Cadmium; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one