Inhibition ofP38pathway-dependent MPTP-induced dopaminergic neurodegeneration in estrogen receptor alpha knockout mice

Chul Ju Hwang^a,1,Dong-Young Choi^b,1,Yu Yeon Jung^a,Young-Jung Lee^c,Jae Suk Yun^d,Ki-Wan Oh^a,Sang-Bae Han^a,Seikwan Oh^e,Mi Hee Park^{a, ,},Jin Tae Hong^{a, ,}

Abstract

Approximately, 7–10 million people in the world suffer fromParkinson's disease(PD). Recently, increasing evidence has suggested the protective effect ofestrogensagainstnigrostriataldopaminergicdamage in PD. In this study, we investigated whetherestrogenaffects1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced behavioral impairment inestrogen receptor alpha(ERα)-deficient mice. MPTP (15 mg/kg, four times with 1.5-h interval)-induced dopaminergicneurodegenerationwas evaluated in ERα wild-type (WT) and knockout (KO) mice. Largerdopaminedepletion, behavioral impairments (Rotarod test, Pole test, andGaittest), activation ofmicrogliaandastrocytes, and neuroinflammation after MPTP injection were observed in ERα KO mice compared to those in WT mice. Immunostaining fortyrosine 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 higherimmunoreactivityformonoamine oxidase(MAO) B was found in thesubstantia nigraandstriatumof ERα KO mice after MPTP injection. We also found an increased activation of p38kinase(which positively regulates MAO B expression) in ERα KO mice.In vitroestrogen treatment inhibited neuroinflammation in 1-methyl-4-phenylpyridium(MPP +)-treated culturedastrocytecells; however, these inhibitory effects were removed byp38 inhibitor. These results indicate that ERα might be important for dopaminergic neuronal survival through inhibition of p38 pathway.

Hormones and Behavior

Volume 80, April 2016, Pages 19–29