Neuroprotective effects of a novel non-receptor-binding estrogen analogue: In vitro and in vivo analysis

Ran Liu, Shao Hua Yang, Evelyn Perez, Kun Don Yi, Samuel S. Wu, Kathleen Eberst, Laszlo Prokai, Katalin Prokai-Tatrai, Zu Yun Cai, Douglas F. Covey, Arthur L. Day, James W. Simpkins

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Background and Purpose - Although estrogens are neuroprotective, hormonal effects limit their clinical application. Estrogen analogues with neuroprotective function but lacking hormonal properties would be more attractive. The present study was undertaken to determine the neuroprotective effects of a novel 2-adamantyl estrogen analogue, ZYC3. Methods - Cytotoxicity was induced in HT-22 cells by 10 mmol/L glutamate. 17β-Estradiol (E2) or ZYC3 was added immediately before the exposure to glutamate. Cell viability was determined by calcein assay. The binding of E2 and ZYC3 to human α (ERα) and β (ERβ) estrogen receptors was determined by ligand competition binding assay. Ischemia/reperfusion injury was induced by temporary middle cerebral artery occlusion (MCAO). E2 or ZYC3 (100 μg/kg) was administered 2 hours or immediately before MCAO, respectively. Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining. Cerebral blood flow was recorded during and within 30 minutes after MCAO by a hydrogen clearance method. Results - ZYC3 significantly decreased toxicity of glutamate with a potency 10-fold that of E2. ZYC3 did not bind to either ERα or ERβ. Infarct volume was significantly reduced to 122.4±17.6 and 83.1±19.3 mm3 in E2 and ZYC3 groups, respectively, compared with 252.6±15.6 mm3 in the ovariectomized group. During MCAO, both E2 and ZYC3 significantly increased cerebral blood flow in the nonischemic side, while no significant differences were found in the ischemic side. However, E2 and ZYC3 significantly increased cerebral blood flow in both sides within 30 minutes after reperfusion. Conclusions - Our study shows that ZYC3, a non-receptor-binding estrogen analogue, possesses both neuroprotective and vasoactive effects, which offers the possibility of clinical application for stroke without the side effects of estrogens. It also suggests that both the neuroprotective and vasoactive effects of estrogen are receptor independent.

Original languageEnglish
Pages (from-to)2485-2491
Number of pages7
JournalStroke
Volume33
Issue number10
DOIs
StatePublished - 1 Oct 2002

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Estradiol Congeners
Cerebrovascular Circulation
Middle Cerebral Artery Infarction
Neuroprotective Agents
Glutamic Acid
Estrogen Receptors
Estrogens
Reperfusion Injury
Reperfusion
Hydrogen
Estradiol
Cell Survival
Stroke
Staining and Labeling
Ligands
In Vitro Techniques

Keywords

  • Cerebral blood flow
  • Estrogens
  • Ischemia
  • Neuroprotection
  • Receptors, estrogen
  • Reperfusion injury

Cite this

Liu, Ran ; Yang, Shao Hua ; Perez, Evelyn ; Yi, Kun Don ; Wu, Samuel S. ; Eberst, Kathleen ; Prokai, Laszlo ; Prokai-Tatrai, Katalin ; Cai, Zu Yun ; Covey, Douglas F. ; Day, Arthur L. ; Simpkins, James W. / Neuroprotective effects of a novel non-receptor-binding estrogen analogue : In vitro and in vivo analysis. In: Stroke. 2002 ; Vol. 33, No. 10. pp. 2485-2491.
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author = "Ran Liu and Yang, {Shao Hua} and Evelyn Perez and Yi, {Kun Don} and Wu, {Samuel S.} and Kathleen Eberst and Laszlo Prokai and Katalin Prokai-Tatrai and Cai, {Zu Yun} and Covey, {Douglas F.} and Day, {Arthur L.} and Simpkins, {James W.}",
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Neuroprotective effects of a novel non-receptor-binding estrogen analogue : In vitro and in vivo analysis. / Liu, Ran; Yang, Shao Hua; Perez, Evelyn; Yi, Kun Don; Wu, Samuel S.; Eberst, Kathleen; Prokai, Laszlo; Prokai-Tatrai, Katalin; Cai, Zu Yun; Covey, Douglas F.; Day, Arthur L.; Simpkins, James W.

In: Stroke, Vol. 33, No. 10, 01.10.2002, p. 2485-2491.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neuroprotective effects of a novel non-receptor-binding estrogen analogue

T2 - In vitro and in vivo analysis

AU - Liu, Ran

AU - Yang, Shao Hua

AU - Perez, Evelyn

AU - Yi, Kun Don

AU - Wu, Samuel S.

AU - Eberst, Kathleen

AU - Prokai, Laszlo

AU - Prokai-Tatrai, Katalin

AU - Cai, Zu Yun

AU - Covey, Douglas F.

AU - Day, Arthur L.

AU - Simpkins, James W.

PY - 2002/10/1

Y1 - 2002/10/1

N2 - Background and Purpose - Although estrogens are neuroprotective, hormonal effects limit their clinical application. Estrogen analogues with neuroprotective function but lacking hormonal properties would be more attractive. The present study was undertaken to determine the neuroprotective effects of a novel 2-adamantyl estrogen analogue, ZYC3. Methods - Cytotoxicity was induced in HT-22 cells by 10 mmol/L glutamate. 17β-Estradiol (E2) or ZYC3 was added immediately before the exposure to glutamate. Cell viability was determined by calcein assay. The binding of E2 and ZYC3 to human α (ERα) and β (ERβ) estrogen receptors was determined by ligand competition binding assay. Ischemia/reperfusion injury was induced by temporary middle cerebral artery occlusion (MCAO). E2 or ZYC3 (100 μg/kg) was administered 2 hours or immediately before MCAO, respectively. Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining. Cerebral blood flow was recorded during and within 30 minutes after MCAO by a hydrogen clearance method. Results - ZYC3 significantly decreased toxicity of glutamate with a potency 10-fold that of E2. ZYC3 did not bind to either ERα or ERβ. Infarct volume was significantly reduced to 122.4±17.6 and 83.1±19.3 mm3 in E2 and ZYC3 groups, respectively, compared with 252.6±15.6 mm3 in the ovariectomized group. During MCAO, both E2 and ZYC3 significantly increased cerebral blood flow in the nonischemic side, while no significant differences were found in the ischemic side. However, E2 and ZYC3 significantly increased cerebral blood flow in both sides within 30 minutes after reperfusion. Conclusions - Our study shows that ZYC3, a non-receptor-binding estrogen analogue, possesses both neuroprotective and vasoactive effects, which offers the possibility of clinical application for stroke without the side effects of estrogens. It also suggests that both the neuroprotective and vasoactive effects of estrogen are receptor independent.

AB - Background and Purpose - Although estrogens are neuroprotective, hormonal effects limit their clinical application. Estrogen analogues with neuroprotective function but lacking hormonal properties would be more attractive. The present study was undertaken to determine the neuroprotective effects of a novel 2-adamantyl estrogen analogue, ZYC3. Methods - Cytotoxicity was induced in HT-22 cells by 10 mmol/L glutamate. 17β-Estradiol (E2) or ZYC3 was added immediately before the exposure to glutamate. Cell viability was determined by calcein assay. The binding of E2 and ZYC3 to human α (ERα) and β (ERβ) estrogen receptors was determined by ligand competition binding assay. Ischemia/reperfusion injury was induced by temporary middle cerebral artery occlusion (MCAO). E2 or ZYC3 (100 μg/kg) was administered 2 hours or immediately before MCAO, respectively. Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining. Cerebral blood flow was recorded during and within 30 minutes after MCAO by a hydrogen clearance method. Results - ZYC3 significantly decreased toxicity of glutamate with a potency 10-fold that of E2. ZYC3 did not bind to either ERα or ERβ. Infarct volume was significantly reduced to 122.4±17.6 and 83.1±19.3 mm3 in E2 and ZYC3 groups, respectively, compared with 252.6±15.6 mm3 in the ovariectomized group. During MCAO, both E2 and ZYC3 significantly increased cerebral blood flow in the nonischemic side, while no significant differences were found in the ischemic side. However, E2 and ZYC3 significantly increased cerebral blood flow in both sides within 30 minutes after reperfusion. Conclusions - Our study shows that ZYC3, a non-receptor-binding estrogen analogue, possesses both neuroprotective and vasoactive effects, which offers the possibility of clinical application for stroke without the side effects of estrogens. It also suggests that both the neuroprotective and vasoactive effects of estrogen are receptor independent.

KW - Cerebral blood flow

KW - Estrogens

KW - Ischemia

KW - Neuroprotection

KW - Receptors, estrogen

KW - Reperfusion injury

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