Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice

Uma Maheswari Selvaraj, Kielen R. Zuurbier, Cody W. Whoolery, Erik J. Plautz, Ken L. Chambliss, Xiangmei Kong, Shanrong Zhang, Sung Hoon Kim, Benita S Katzenellenbogen, John A. Katzenellenbogen, Chieko Mineo, Philip W. Shaul, Ann M. Stowe

Research output: Contribution to journalArticle

Abstract

Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.

Original languageEnglish (US)
Pages (from-to)3848-3859
Number of pages12
JournalEndocrinology
Volume159
Issue number11
DOIs
StatePublished - Jan 1 2018

Fingerprint

Estrogen Receptors
Estrogens
Middle Cerebral Artery Infarction
Stroke
Uterine Neoplasms
Brain
Leukocytes
Estrogen Receptor Modulators
Neurogenesis
Blood Vessels
Estradiol
Flow Cytometry
Transcription Factors
Spleen
Animal Models
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Endocrinology

Cite this

Selvaraj, U. M., Zuurbier, K. R., Whoolery, C. W., Plautz, E. J., Chambliss, K. L., Kong, X., ... Stowe, A. M. (2018). Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice. Endocrinology, 159(11), 3848-3859. https://doi.org/10.1210/en.2018-00600

Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice. / Selvaraj, Uma Maheswari; Zuurbier, Kielen R.; Whoolery, Cody W.; Plautz, Erik J.; Chambliss, Ken L.; Kong, Xiangmei; Zhang, Shanrong; Kim, Sung Hoon; Katzenellenbogen, Benita S; Katzenellenbogen, John A.; Mineo, Chieko; Shaul, Philip W.; Stowe, Ann M.

In: Endocrinology, Vol. 159, No. 11, 01.01.2018, p. 3848-3859.

Research output: Contribution to journalArticle

Selvaraj, UM, Zuurbier, KR, Whoolery, CW, Plautz, EJ, Chambliss, KL, Kong, X, Zhang, S, Kim, SH, Katzenellenbogen, BS, Katzenellenbogen, JA, Mineo, C, Shaul, PW & Stowe, AM 2018, 'Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice', Endocrinology, vol. 159, no. 11, pp. 3848-3859. https://doi.org/10.1210/en.2018-00600
Selvaraj, Uma Maheswari ; Zuurbier, Kielen R. ; Whoolery, Cody W. ; Plautz, Erik J. ; Chambliss, Ken L. ; Kong, Xiangmei ; Zhang, Shanrong ; Kim, Sung Hoon ; Katzenellenbogen, Benita S ; Katzenellenbogen, John A. ; Mineo, Chieko ; Shaul, Philip W. ; Stowe, Ann M. / Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice. In: Endocrinology. 2018 ; Vol. 159, No. 11. pp. 3848-3859.
@article{a892c8c4648a424e984d3ad6a96dabf7,
title = "Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice",
abstract = "Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.",
author = "Selvaraj, {Uma Maheswari} and Zuurbier, {Kielen R.} and Whoolery, {Cody W.} and Plautz, {Erik J.} and Chambliss, {Ken L.} and Xiangmei Kong and Shanrong Zhang and Kim, {Sung Hoon} and Katzenellenbogen, {Benita S} and Katzenellenbogen, {John A.} and Chieko Mineo and Shaul, {Philip W.} and Stowe, {Ann M.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1210/en.2018-00600",
language = "English (US)",
volume = "159",
pages = "3848--3859",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "11",

}

TY - JOUR

T1 - Selective Nonnuclear Estrogen Receptor Activation Decreases Stroke Severity and Promotes Functional Recovery in Female Mice

AU - Selvaraj, Uma Maheswari

AU - Zuurbier, Kielen R.

AU - Whoolery, Cody W.

AU - Plautz, Erik J.

AU - Chambliss, Ken L.

AU - Kong, Xiangmei

AU - Zhang, Shanrong

AU - Kim, Sung Hoon

AU - Katzenellenbogen, Benita S

AU - Katzenellenbogen, John A.

AU - Mineo, Chieko

AU - Shaul, Philip W.

AU - Stowe, Ann M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.

AB - Estrogens provide neuroprotection in animal models of stroke, but uterotrophic effects and cancer risk limit translation. Classic estrogen receptors (ERs) serve as transcription factors, whereas nonnuclear ERs govern numerous cell processes and exert beneficial cardiometabolic effects without uterine or breast cancer growth in mice. Here, we determined how nonnuclear ER stimulation with pathway-preferential estrogen (PaPE)-1 affects stroke outcome in mice. Ovariectomized female mice received vehicle, estradiol (E2), or PaPE-1 before and after transient middle cerebral artery occlusion (tMCAo). Lesion severity was assessed with MRI, and poststroke motor function was evaluated through 2 weeks after tMCAo. Circulating, spleen, and brain leukocyte subpopulations were quantified 3 days after tMCAo by flow cytometry, and neurogenesis and angiogenesis were evaluated histologically 2 weeks after tMCAo. Compared with vehicle, E2 and PaPE-1 reduced infarct volumes at 3 days after tMCAo, though only PaPE-1 reduced leukocyte infiltration into the ischemic brain. Unlike E2, PaPE-1 had no uterotrophic effect. Both interventions had negligible effect on long-term poststroke neuronal or vascular plasticity. All mice displayed a decline in motor performance at 2 days after tMCAo, and vehicle-treated mice did not improve thereafter. In contrast, E2 and PaPE-1 treatment afforded functional recovery at 6 days after tMCAo and beyond. Thus, the selective activation of nonnuclear ER by PaPE-1 decreased stroke severity and improved functional recovery in mice without undesirable uterotrophic effects. The beneficial effects of PaPE-1 are also associated with attenuated neuroinflammation in the brain. PaPE-1 and similar molecules may warrant consideration as efficacious ER modulators providing neuroprotection without detrimental effects on the uterus or cancer risk.

UR - http://www.scopus.com/inward/record.url?scp=85055616892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055616892&partnerID=8YFLogxK

U2 - 10.1210/en.2018-00600

DO - 10.1210/en.2018-00600

M3 - Article

VL - 159

SP - 3848

EP - 3859

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 11

ER -