title: Estrogen attenuates manganese-induced glutamate transporter impairment in rat primary astrocytes.
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.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA. elee@mmc.edu
authors.forename: Eunsook
authors.initials: E
authors.lastname: Lee
authors.forename: Marta
authors.initials: M
authors.lastname: Sidoryk-Wegrzynowicz
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Joao B T
authors.initials: JB
authors.lastname: Rocha
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008345:Manganese / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; D004967:Estrogens; C520305:Gper1 protein, rat; D043562:Receptors, G-Protein-Coupled; D008345:Manganese