17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity

Edward Pajarillo, James Johnson, Judong Kim, Pratap Karki, Deok Soo Son, Michael Aschner, Eunsook Lee

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.

Original languageEnglish (US)
JournalNeuroToxicology
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Tamoxifen
Manganese
Estradiol
Amino Acid Transport System X-AG
Excitatory Amino Acid Transporter 1
Selective Estrogen Receptor Modulators
Oxidative stress
Growth Factor Receptors
Dopaminergic Neurons
Parkinsonian Disorders
Transforming Growth Factors
Substantia Nigra
Locomotion
Nervous System Diseases
Malondialdehyde
Inbred C57BL Mouse
Catalase
Neurons
Glutathione
Parkinson Disease

Keywords

  • 17β-estradiol
  • GLAST
  • GLT-1
  • Manganese
  • Tamoxifen
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity. / Pajarillo, Edward; Johnson, James; Kim, Judong; Karki, Pratap; Son, Deok Soo; Aschner, Michael; Lee, Eunsook.

In: NeuroToxicology, 01.01.2017.

Research output: Contribution to journalArticle

Pajarillo, Edward ; Johnson, James ; Kim, Judong ; Karki, Pratap ; Son, Deok Soo ; Aschner, Michael ; Lee, Eunsook. / 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity. In: NeuroToxicology. 2017.
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AU - Johnson, James

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AU - Son, Deok Soo

AU - Aschner, Michael

AU - Lee, Eunsook

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