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ToxSci Advance Access originally published online on May 13, 2008
Toxicological Sciences 2008 104(2):352-361; doi:10.1093/toxsci/kfn092
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Rotenone-Induced Toxicity is Mediated by Rho-GTPases in Hippocampal Neurons

Monica Sanchez*,{dagger}, Laura Gastaldi{dagger}, Monica Remedi{dagger}, Alfredo Cáceres{dagger},1 and Carlos Landa*

* Unidad CEPROCOR, Agencia Cordoba Ciencia, Córdoba {dagger} Laboratory Neurobiologia, Instituto Investigacion Medica Mercedes y Martín Ferreyra (INIMEC-CONICET), Córdoba, Argentina

1 To whom correspondence should be addressed at Laboratory Neurobiologia, Instituto Investigacion Medica Mercedes y Martin Ferreyra (INIMEC-CONICET), Cordoba, Argentina. E-mail: acaceres{at}immf.uncor.edu.

Received February 21, 2008; accepted May 5, 2008


  Abstract

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 (0.1µM) 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.

Key Words: rotenone; neurons; axons; polarity; small Rho-GTPases.


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