Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons.

SANCHEZ, MÓNICA; GASTALDI, LAURA; REMEDI, MÓNICA; CACERES, ALFREDO; LANDA, CARLOS

JOURNAL OF TOXICOLOGICAL SCIENCES, THE

Oxford University Press,

Lugar: United States; Año: 2008 vol. 104 p. 352 - 361

0388-1350

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 uM) 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.