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Estrogen Attenuates Manganese-Induced Glutamate Transporter Impairment in Rat Primary Astrocytes

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Abstract

The astrocytic glutamate transporters (GLT-1, GLAST) are critical for removing excess glutamate from synaptic sites, thereby maintaining glutamate homeostasis within the brain. 17β-Estradiol (E2) is one of the most active estrogen hormones possessing neuroprotective effects both in in vivo and in vitro models, and it has been shown to enhance astrocytic glutamate transporter function (Liang et al. in J Neurochem 80:807–814, 2002; Pawlak et al. in Brain Res Mol Brain Res 138:1–7, 2005). However, E2 is not clinically optimal for neuroprotection given its peripheral feminizing and proliferative effects; therefore, brain selective estrogen receptor modulators (neuro SERMs) (Zhao et al. in Neuroscience 132:299–311, 2005) that specifically target estrogenic mechanisms, but lack the systemic estrogen side effects offer more promising therapeutic modality for the treatment of conditions associated with excessive synaptic glutamate levels. This review highlights recent studies from our laboratory showing that E2 and SERMs effectively reverse glutamate transport inhibition in a manganese (Mn)-induced model of glutamatergic deregulation. Specifically, we discuss mechanisms by which E2 restores the expression and activity of glutamate uptake. We advance the hypothesis that E2 and related compounds, such as tamoxifen may offer a potential therapeutic modality in neurodegenerative disorders, which are characterized by altered glutamate homeostasis.

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Acknowledgments

This review was supported in part by grants from the National Institutes of Health (NIH) ES R01 10563, ES P30 000267 and GM SC1 089630.

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Authors and Affiliations

  1. Department of Physiology, Meharry Medical College, Nashville, TN, 37208, USA

    Eunsook Lee

  2. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    Marta Sidoryk-Wegrzynowicz & Michael Aschner

  3. Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Marcelo Farina

  4. Departamento de Bioquímica, CCNE, Universidade de Santa Maria, Santa Maria, RS, Brazil

    Joao B. T. Rocha

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  1. Eunsook Lee
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Correspondence to Eunsook Lee.

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Lee, E., Sidoryk-Wegrzynowicz, M., Farina, M. et al. Estrogen Attenuates Manganese-Induced Glutamate Transporter Impairment in Rat Primary Astrocytes. Neurotox Res 23, 124–130 (2013). https://doi.org/10.1007/s12640-012-9347-2

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