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ToxSci Advance Access published online on April 21, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp081
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Estrogen and tamoxifen protect against Mn-induced toxicity in rat cortical primary cultures of neurons and astrocytes

Eun-Sook Y. Lee*,§, Zhaobao Yin{ddagger}, Dejan Milatovic{ddagger}, Haiyan Jiang{ddagger} and Michael Aschner{ddagger}

§ Department of Neurology, School of Medicine, Meharry Medical College {ddagger} Department of Pediatrics, Vanderbilt Medical Center, Vanderbilt University

* Correspondence should be addressed to: Dr. Eun-Sook Y. Lee, Department of Neurology, Meharry Medical College, Nashville, TN 37208, Tel.: (615) 327-6056, Fax: (615) 327-5711, e-mail address: elee{at}mmc.edu

Received February 26, 2009; revision received April 9, 2009; accepted April 10, 2009


  Abstract

Chronic exposure to manganese (Mn) leads to a neurological disorder, manganism, which shares multiple common features with idiopathic Parkinson's disease (PD). 17β-Estradiol (E2) and some selective estrogen receptor modulators (SERMs), including tamoxifen (TX), afford neuroprotection in various experimental models of neurodegeneration. However, the neuroprotective effects and mechanisms of E2/TX in Mn-induced toxicity have yet to be documented. Herein, we studied the ability of E2/TX to protect rat cortical primary neuronal and astroglial cultures from Mn-induced toxicity. Cell viability, western blot and reactive oxygen species (ROS) generation were assessed. Results established that both E2 (10 nM) and TX (1 µM) attenuated Mn-induced toxicity. The protective effects of E2/TX were more pronounced in astrocytes vs. neurons. The E2-mediated attenuation of Mn-induced ROS generation in astrocytes at 6 h treatment (where no cell death was detected) was mediated by a classical estrogen receptor (ER) pathway and the TX-mediated effect on Mn-induced ROS generation was not mediated via classical ER-dependent mechanisms, and likely by its antioxidant properties. The phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway was involved in both E2- and TX-induced attenuation of Mn-induced ROS formation (6 h) in astrocytes. Treatments with Mn for a longer duration (24 h) led to significant cell death and the protective effects of E2 and TX were (1) not mediated by a classical ER-pathway, and (2) associated with activation of both mitogen-activated protein kinase (MAPK)/ERK and PI3K/Akt signaling pathways. Taken together, the results suggest that both E2 and TX offer effective therapeutic means for neuroprotection against Mn-induced toxicity.

Key Words: neuroprotection; oxidative stress; MAPK/ERK; PI3K/Akt; tamoxifen; 17β-estradiol.


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