title: Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel.
abstract: Microglial activation is implicated in the pathogenesis of Parkinson's disease (PD). Although the etiology of PD remains unclear, age and male gender are known PD risk factors. By comparing microglia and dopaminergic (DA) neurons in the substantia nigra (SN) of male and female mice of different ages, we found that the degrees of microglial activation and DA neuron loss increased with age in both genders, but were more pronounced in males, as were peripheral lipopolysaccharide (LPS)-induced microglial activation and DA neuron loss. A bilateral ovariectomy (OVX) eliminated the female-associated protection against age- and LPS-induced microglial activation, which suggests that ovary hormones are involved in gender-specific responses. Treating female mice with 17β-estradiol supplements reduced the age-associated microglial activation in OVX mice. Moreover, pretreating mouse BV2 microglial cells with 17β-estradiol inhibited LPS-induced elevation of Toll-like receptor 4, phosphorylated p38, and TNF-α levels. We then examined the effect of 17β-estradiol on inward-rectifier K(+) channel Kir2.1, a known regulator of microglial activation. We found that 17β-estradiol inhibited the Kir2.1 activity of BV2 cells by reducing the probability that the channel would be open. We conclude that age- and inflammation-associated microglial activation is attenuated by ovarian estrogen, because it inhibits Kir2.1.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Ying
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, Taiwan.|Department of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sheng-Feng
authors.initials: SF
authors.lastname: Tsai
authors.affiliation: Department of Physiology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yao-Hsiang
authors.initials: YH
authors.lastname: Shih
authors.affiliation: Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Jiang-Shieh
authors.affiliation: Department of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yang
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.|Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Kuo
mesh_terms: D000367:Age Factors; D000818:Animals; D002452:Cell Count; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012737:Sex Factors; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D004967:Estrogens; D008070:Lipopolysaccharides; D024661:Potassium Channels, Inwardly Rectifying; D004958:Estradiol