Inhibition of p38 pathway-dependent MPTP-induced dopaminergic neurodegeneration in estrogen receptor alpha knockout mice

Chul Ju Hwang, Dong Young Choi, Yu Yeon Jung, Young Jung Lee, Jae Suk Yun, Ki Wan Oh, Sang Bae Han, Seikwan Oh, Mi Hee Park, Jin Tae Hong

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5 Scopus citations


Approximately, 7-10 million people in the world suffer from Parkinson's disease (PD). Recently, increasing evidence has suggested the protective effect of estrogens against nigrostriatal dopaminergic damage in PD. In this study, we investigated whether estrogen affects 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment in estrogen receptor alpha (ERα)-deficient mice. MPTP (15 mg/kg, four times with 1.5-h interval)-induced dopaminergic neurodegeneration was evaluated in ERα wild-type (WT) and knockout (KO) mice. Larger dopamine depletion, behavioral impairments (Rotarod test, Pole test, and Gait test), activation of microglia and astrocytes, and neuroinflammation after MPTP injection were observed in ERα KO mice compared to those in WT mice. Immunostaining for tyrosine hydroxylase (TH) after MPTP injection showed fewer TH-positive neurons in ERα KO mice than WT mice. Levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC, metabolite of dopamine) were also lowered in ERα KO mice after MPTP injection. Interestingly, a higher immunoreactivity for monoamine oxidase (MAO) B was found in the substantia nigra and striatum of ERα KO mice after MPTP injection. We also found an increased activation of p38 kinase (which positively regulates MAO B expression) in ERα KO mice. In vitro estrogen treatment inhibited neuroinflammation in 1-methyl-4-phenyl pyridium (MPP. +)-treated cultured astrocyte cells; however, these inhibitory effects were removed by p38 inhibitor. These results indicate that ERα might be important for dopaminergic neuronal survival through inhibition of p38 pathway.

Original languageEnglish
Pages (from-to)19-29
Number of pages11
JournalHormones and Behavior
StatePublished - 1 Apr 2016

Bibliographical note

Funding Information:
This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the South Korean Government (MSIP; MRC, 2008-0062275 ) and the Marine Biotechnology Program ( 20150184 ) funded by Ministry of Oceans and Fisheries, South Korea .

Publisher Copyright:
© 2016 Published by Elsevier Inc.


  • Estrogen
  • Estrogen receptor alpha
  • MAO
  • P38
  • Parkinson's disease


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