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ToxSci Advance Access published online on May 13, 2008
Toxicological Sciences, 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 Sanchez1,2, Laura Gastaldi2, Monica Remedi2, Alfredo Cáceres2,* and Carlos Landa1,*

1 Unidad CEPROCOR, Agencia Cordoba Ciencia, Córdoba 2 Laboratory Neurobiologia, Instituto Investigacion Medica Mercedes y Martín Ferreyra (INIMEC-CONICET), Córdoba, Argentina

* Corresponding Authors: Alfredo Cáceres, Instituto Investigacion Medica Mercedes y Martín Ferreyra (INIMEC-CONICET), Av. Friuli 2434, 5016 Cordoba, ARGENTINA, Phone: 54-351-4681465, E-mail: acaceres{at}immf.uncor.edu

Carlos Landa, CEPROCOR—Agencia Córdoba Ciencia, Complejo Hospitalario Santa María de Punilla, 5164, Santa María de Punilla, Córdoba, Argentina, E-mail: clanda{at}powernet.net.ar

Received February 21, 2008; revision received May 4, 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-hour exposure to rotenone (0.1 µM) 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, while 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 Tiam 1, 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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