Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes

Eun Sook Y Lee, Marta Sidoryk, Haiyan Jiang, Zhaobao Yin, Michael Aschner

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Chronic exposure to manganese (Mn) can cause manganism, a neurodegenerative disorder similar to Parkinson's disease. The toxicity of Mn includes impairment of astrocytic glutamate transporters. 17β-Estradiol (E2) has been shown to be neuroprotective in various neurodegenerative diseases including Parkinson's disease and Alzheimer's disease, and some selective estrogen receptor modulators, including tamoxifen (TX), also possess neuroprotective properties. We have tested our hypothesis that E2 and TX reverse Mn-induced glutamate transporter impairment in astrocytes. The results established that E2 and TX increased glutamate transporter function and reversed Mn-induced glutamate uptake inhibition, primarily via the up-regulation of glutamate/aspartate transporter (GLAST). E2 and TX also increased astrocytic GLAST mRNA levels and attenuated the Mn-induced inhibition of GLAST mRNA expression. In addition, E2 and TX effectively increased the expression of transforming growth factor β1, a potential modulator of the stimulatory effects of E2/TX on glutamate transporter function. This effect was mediated by the activation of MAPK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways. These novel findings suggest, for the first time, that E2 and TX enhance astrocytic glutamate transporter expression via increased transforming growth factor β1 expression. Furthermore, the present study is the first to show that both E2 and TX effectively reverse Mn-induced glutamate transport inhibition by restoring its expression and activity, thus offering a potential therapeutic modality in neurodegenerative disorders characterized by altered glutamate homeostasis.

Original languageEnglish (US)
Pages (from-to)530-544
Number of pages15
JournalJournal of Neurochemistry
Volume110
Issue number2
DOIs
StatePublished - Jul 2009
Externally publishedYes

Fingerprint

Amino Acid Transport System X-AG
Tamoxifen
Manganese
Astrocytes
Estrogens
Neurodegenerative Diseases
Glutamic Acid
Transforming Growth Factors
Parkinson Disease
Mitogen-Activated Protein Kinase 6
Neurodegenerative diseases
Selective Estrogen Receptor Modulators
Messenger RNA
1-Phosphatidylinositol 4-Kinase
Extracellular Signal-Regulated MAP Kinases
Phosphatidylinositols
Modulators
Toxicity
Estradiol
Alzheimer Disease

Keywords

  • 17β-estradiol
  • Astrocytes
  • Astroglial glutamate transporters
  • Glutamate transporters
  • Tamoxifen
  • Transforming growth factor-β1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes. / Lee, Eun Sook Y; Sidoryk, Marta; Jiang, Haiyan; Yin, Zhaobao; Aschner, Michael.

In: Journal of Neurochemistry, Vol. 110, No. 2, 07.2009, p. 530-544.

Research output: Contribution to journalArticle

Lee, Eun Sook Y ; Sidoryk, Marta ; Jiang, Haiyan ; Yin, Zhaobao ; Aschner, Michael. / Estrogen and tamoxifen reverse manganese-induced glutamate transporter impairment in astrocytes. In: Journal of Neurochemistry. 2009 ; Vol. 110, No. 2. pp. 530-544.
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