Rotenone-induced toxicity is mediated by Rho-GTPases in hippocampal neurons
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 (0.1 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.
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In primary rat hippocampal and dopaminergic neuronal cultures treated with rotenone, RhoA activity is increased and associated with reduced neurite outgrowth, which is normalized by ROCK inhibition using Y27632.
“In primary rat hippocampal and dopaminergic neuronal cultures treated with the neurotoxic pesticide rotenone, RhoA activity was increased and associated with reduced neurite outgrowth, which was normalized by ROCK inhibition using Y27632 [169].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [169]
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- Authors
- Sanchez, M., Gastaldi, L., Remedi, M., Cáceres, A., & Landa, C.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Centro de Excelencia en Procesos y Productos de Córdoba (AR)
- Corresponding author
- Cáceres, Alfredo
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-05-13
- Volume
- 104
- Issue
- 2
- Pages
- 352-361
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2160365260
- Cited by
- 60
- References
- 0
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 5
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- rotenone, neurotoxicity, Rho GTPases, hippocampal neurons, dopaminergic neurons, axon formation, Cdc42, Rac, Rho, actin dynamics, Tiam1, Rho kinase, pesticide toxicity, cytochalasin D
- MeSH terms
- Amides, Animals, Axons, Cell Count, Cells, Cultured, Dopamine, Dose-Response Relationship, Drug, Enzyme Inhibitors, Fetus, Herbicides, Pyridines, Rotenone, Cytochalasin D, Neurites, Pyramidal Cells, Recovery of Function, rho GTP-Binding Proteins, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, Rats
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