Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons.
In this study, we have examined the effects of rotenone in primary cultures of hippocampal and dopaminergic neurons in order to obtain insights into the possible mechanisms underlying the neurotoxic effects of this pesticide. The results obtained indicate that a 48-h exposure to rotenone (0.1 microM) produces a complete and selective suppression of axon formation. This effect was dose dependent, not accompanied by changes in microtubule organization, and reversible after washout of the agrochemical from the tissue culture medium. Interestingly, pull-down assays revealed that rotenone decreases Cdc42 and Rac activities, whereas increasing that of Rho. In accordance with this, treatment of neuronal cultures with cytochalasin D, an actin-depolymerizing drug, or with the Rho-kinase inhibitor Y27632, or overexpression of Tiam1, a guanosine nucleotide exchange factor for Rac, reverts the inhibitory effect of rotenone on axon formation. Taken together, our data suggest that at least some of the neurotoxic effects of rotenone are associated with an inhibition of actin dynamics through modifications of Rho-GTPase activity.
Sanchez
Monica
M
Unidad CEPROCOR, Agencia Cordoba Ciencia, Córdoba, Argentina.
Gastaldi
Laura
L
Remedi
Monica
M
Cáceres
Alfredo
A
Landa
Carlos
C
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D006540:Herbicides / Q000633:toxicity*; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020127:Recovery of Function; D012402:Rotenone / Q000633:toxicity*; D020764:cdc42 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism
D000577:Amides; D004791:Enzyme Inhibitors; D006540:Herbicides; D011725:Pyridines; D012402:Rotenone; C108830:Y 27632; D015638:Cytochalasin D; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D004298:Dopamine