Medroxyprogesterone Acetate Antagonizes Estrogen Up-Regulation of Brain Mitochondrial Function
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- Ronald W. Irwin
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
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- Jia Yao
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
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- Syeda S. Ahmed
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
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- Ryan T. Hamilton
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
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- Enrique Cadenas
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
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- Roberta Diaz Brinton
- Department of Pharmacology and Pharmaceutical Sciences (R.W.I., J.Y., S.S.A., R.H., E.C., R.D.B.), University of Southern California, Los Angeles, California 90033
抄録
<jats:title>Abstract</jats:title><jats:p>The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women. Previous analyses indicated that progesterone and 17β-estradiol (E2) sustain and enhance brain mitochondrial energy-transducing capacity. Herein we determined the impact of the clinical progestin, medroxyprogesterone acetate (MPA), on glycolysis, oxidative stress, and mitochondrial function in brain. Ovariectomized female rats were treated with MPA, E2, E2+MPA, or vehicle with ovary-intact rats serving as a positive control. MPA alone and MPA plus E2 resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase, and peroxiredoxin V. MPA alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the coadministration of E2 and MPA exhibited moderate efficacy. However, the coadministration of MPA was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression. Accumulated lipid peroxides were cleared by E2 treatment alone but not in combination with MPA. Furthermore, MPA abolished E2-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia. Collectively these findings indicate that the effects of MPA differ significantly from the bioenergetic profile induced by progesterone and that, overall, MPA induced a decline in glycolytic and oxidative phosphorylation protein and activity. These preclinical findings on the basis of acute exposure to MPA raise concerns regarding neurological health after chronic use of MPA in contraceptive and hormone therapy.</jats:p>
収録刊行物
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- Endocrinology
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Endocrinology 152 (2), 556-567, 2010-12-15
The Endocrine Society
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キーワード
詳細情報 詳細情報について
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- CRID
- 1360292619242520704
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- ISSN
- 19457170
- 00137227
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- データソース種別
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- Crossref