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Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naive postmenopausal Parkinson's disease.

ABSTRACT: This study aimed to investigate the potential beneficial effects of estrogen on nigrostriatal dopaminergic neuron degeneration in postmenopausal drug-naïve Parkinson's disease (PD). Based on the ratio of lifetime estrogen exposure length to the total length of the estrogen exposure and deprivation period, postmenopausal women with drug-naïve PD were divided into low (n?=?31) and high (n?=?31) estrogen exposure ratio groups. We performed a comparative analysis of the striatal dopamine transporter (DAT) availability between the two groups. Additionally, we evaluated the longitudinal change in the levodopa equivalent dose per month using a linear mixed model. The motor symptoms were more severe in the low estrogen exposure ratio group than in the high estrogen exposure ratio group (P?=?0.016). PD patients in the two groups had significantly lower DAT availability on all striatal sub-regions except for ventral striatum than did age- and sex-matched normal controls. When comparing the two groups, PD patients in the low estrogen exposure ratio group exhibited significantly lower DAT availability in the posterior putamen (P?=?0.024) and in the ventral putamen (P?=?0.036) than those in the high estrogen exposure ratio group. The estimated monthly levodopa equivalent dose changes were 10.9 in the low estrogen exposure ratio group and 7.1 in the high estrogen exposure ratio group with a significant interaction between the two groups (P?=?0.001). These in vivo data provide indirect evidence showing that estrogen may elicit a beneficial effect on nigrostriatal dopamine neurons in PD.

SUBMITTER: Lee YH

PROVIDER: S-EPMC6642214 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naïve postmenopausal Parkinson's disease.

Lee Yang Hyun YH Cha Jungho J Chung Seok Jong SJ Yoo Han Soo HS Sohn Young H YH Ye Byoung Seok BS Lee Phil Hyu PH

Scientific reports 20190719 1

This study aimed to investigate the potential beneficial effects of estrogen on nigrostriatal dopaminergic neuron degeneration in postmenopausal drug-naïve Parkinson's disease (PD). Based on the ratio of lifetime estrogen exposure length to the total length of the estrogen exposure and deprivation period, postmenopausal women with drug-naïve PD were divided into low (n = 31) and high (n = 31) estrogen exposure ratio groups. We performed a comparative analysis of the striatal dopamine transporter ...[more]

PMID: 31324895

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Project description:ObjectiveThe dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia.MethodsRats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.ResultsThe selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.ConclusionsThe present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

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Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naive postmenopausal Parkinson's disease.

Publications

Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naïve postmenopausal Parkinson's disease.

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