title: Inhibition of p38 pathway-dependent MPTP-induced dopaminergic neurodegeneration in estrogen receptor alpha knockout mice.
abstract: 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 (15mg/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.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea.
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Yeungnam University, 280, Daehak-ro, Gyeongsan, Gyeongbuk 712-749, South Korea.
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea.
authors.forename: Yu Yeon
authors.initials: YY
authors.lastname: Jung
authors.affiliation: School of Equine Science, Cheju Halla University, 38 Halladaehak-ro, Jeju-si, Jeju Special Self-Governing Province 690-708, South Korea.
authors.forename: Young-Jung
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Osong Health Technology Administration Complex, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Cheongju, Chungbuk 363-700, South Korea.
authors.forename: Jae Suk
authors.initials: JS
authors.lastname: Yun
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea.
authors.forename: Ki-Wan
authors.initials: KW
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Neuroscience and Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul 158-710, South Korea.
authors.forename: Seikwan
authors.initials: S
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea. Electronic address: pmh5205@hanmail.net.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 361-951, South Korea. Electronic address: jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics*; D010300:Parkinson Disease / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Estrogen; Estrogen receptor alpha; MAO; P38; Parkinson's disease