Repression of adenosine triphosphate binding cassette transporter ABCG2 by estrogen increases intracellular glutathione in brain endothelial cells following ischemic reperfusion injury

Over my head but it talks about neuroprotection against ischemic injury, so go ask your doctor whom she is following up with to get this tested in humans.
https://www.sciencedirect.com/science/article/pii/S0197458018300642

• Jin A. Shin^{a, 1},
• Sae Im Jeong^{b, 1},
• Hye Won Kim^a,
• Gyeonghui Jang^a,
• Dong-Ryeol Ryu^c,
• Young-Ho Ahn^d,
• Ji Ha Choi^a,
• Youn-Hee Choi^e,
• Eun-Mi Park^{a, ,}

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https://doi.org/10.1016/j.neurobiolaging.2018.02.020

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Highlights

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Estrogen decreased basal protein level of ABCG2 in the brain of OVX mice.

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Estrogen prevented ischemia-induced brain ABCG2 level in OVX mice.

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ABCG2 siRNA transfection reduced OGD-induced injury in bEnd.3 cells.

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Estrogen enhanced survival in bEnd.3 cells transfected with ABCG2 siRNA against OGD.

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ABCG2 inhibition increased intracellular glutathione in bEnd.3 cells exposed to OGD.

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Abstract

The adenosine triphosphate-binding cassette efflux transporter ABCG2 which is located in the blood-brain barrier limits the entry of endogenous compounds and xenobiotics into the brain, and its expression and activity are regulated by estrogen. This study was aimed to define the role of ABCG2 in estrogen-mediated neuroprotection against ischemic injury. ABCG2 protein levels before and after ischemic stroke were increased in the brain of female mice by ovariectomy, which were reversed by estrogen replacement. In brain endothelial cell line bEnd.3, estrogen reduced the basal ABCG2 protein level and efflux activity, and protected cells from ischemic injury without inducing ABCG2 expression. When bEnd.3 cells were transfected with ABCG2 small interfering RNA (siRNA), ischemia-induced cell death was reduced, and the intracellular concentration of glutathione, an antioxidant that is transported by ABCG2, was increased. In addition, after ischemic stroke in ovariectomized mice, estrogen prevented the reduction of intracellular glutathione level in brain microvessels. These data suggested that the suppression of ABCG2 by estrogen is involved in neuroprotection against ischemic injury by increasing intracellular glutathione, and that the modulation of ABCG2 activity offers a therapeutic target for brain diseases in estrogen-deficient aged women.

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Graphical abstract

Keywords

• ABCG2;
• brain endothelial cell;
• estrogen;
• glutathione;
• ischemic stroke;
• neuroprotection

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1. All authors disclose that there are no actual or potential conflicts of interest.

2. This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) (2010-0011353 and 2014R1A2A1A11051461).

3. The data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging.

4. Animal experiments in the present paper comply with the NIH and Ewha Womans University guidelines for Laboratory Animals Care and Use, and the study was approved by the Institutional Animal Care and Use Committee of the Medical School of Ewha Womans University.

5. All authors have reviewed the contents of the manuscript being submitted, approve of its contents and validate the accuracy of the data.

Corresponding author: Eun-Mi Park, Department of Pharmacology, Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, 07985, Republic of Korea, Tel.: 82-2-2650-5743, Fax: 82-2-2653-8891.