Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection

Louise D. McCullough, Kathleen Blizzard, Evan R. Simpson, Orhan K. Öz, Patricia D. Hurn

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8%; cortical, 47.4 ± 5.7%; striatal, 44.8 ± 7.8%) compared with WT (total, 14.2 ± 5%; cortical, 14.2 ± 4.5%; striatal, 17.5 ± 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17β-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

Original languageEnglish (US)
Pages (from-to)8701-8705
Number of pages5
JournalJournal of Neuroscience
Volume23
Issue number25
StatePublished - Sep 24 2003

Fingerprint

Aromatase
Cytochrome P-450 Enzyme System
Estrogens
Corpus Striatum
Estradiol
Wounds and Injuries
Fadrozole
Neuroprotection
Aromatase Inhibitors
Middle Cerebral Artery Infarction
Knockout Mice
Androgens
Reperfusion
Perfusion
Blood Pressure

Keywords

  • Aromatase
  • Estrogen
  • Gender
  • Ischemia
  • Neuroprotection
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

McCullough, L. D., Blizzard, K., Simpson, E. R., Öz, O. K., & Hurn, P. D. (2003). Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. Journal of Neuroscience, 23(25), 8701-8705.

Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. / McCullough, Louise D.; Blizzard, Kathleen; Simpson, Evan R.; Öz, Orhan K.; Hurn, Patricia D.

In: Journal of Neuroscience, Vol. 23, No. 25, 24.09.2003, p. 8701-8705.

Research output: Contribution to journalArticle

McCullough, LD, Blizzard, K, Simpson, ER, Öz, OK & Hurn, PD 2003, 'Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection', Journal of Neuroscience, vol. 23, no. 25, pp. 8701-8705.
McCullough, Louise D. ; Blizzard, Kathleen ; Simpson, Evan R. ; Öz, Orhan K. ; Hurn, Patricia D. / Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 25. pp. 8701-8705.
@article{ca1b05f52c49478898a206ae77ca3c53,
title = "Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection",
abstract = "Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8{\%}; cortical, 47.4 ± 5.7{\%}; striatal, 44.8 ± 7.8{\%}) compared with WT (total, 14.2 ± 5{\%}; cortical, 14.2 ± 4.5{\%}; striatal, 17.5 ± 8{\%}). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17β-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.",
keywords = "Aromatase, Estrogen, Gender, Ischemia, Neuroprotection, Stroke",
author = "McCullough, {Louise D.} and Kathleen Blizzard and Simpson, {Evan R.} and {\"O}z, {Orhan K.} and Hurn, {Patricia D.}",
year = "2003",
month = "9",
day = "24",
language = "English (US)",
volume = "23",
pages = "8701--8705",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "25",

}

TY - JOUR

T1 - Aromatase cytochrome P450 and extragonadal estrogen play a role in ischemic neuroprotection

AU - McCullough, Louise D.

AU - Blizzard, Kathleen

AU - Simpson, Evan R.

AU - Öz, Orhan K.

AU - Hurn, Patricia D.

PY - 2003/9/24

Y1 - 2003/9/24

N2 - Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8%; cortical, 47.4 ± 5.7%; striatal, 44.8 ± 7.8%) compared with WT (total, 14.2 ± 5%; cortical, 14.2 ± 4.5%; striatal, 17.5 ± 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17β-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

AB - Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8%; cortical, 47.4 ± 5.7%; striatal, 44.8 ± 7.8%) compared with WT (total, 14.2 ± 5%; cortical, 14.2 ± 4.5%; striatal, 17.5 ± 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17β-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

KW - Aromatase

KW - Estrogen

KW - Gender

KW - Ischemia

KW - Neuroprotection

KW - Stroke

UR - http://www.scopus.com/inward/record.url?scp=0141535178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141535178&partnerID=8YFLogxK

M3 - Article

VL - 23

SP - 8701

EP - 8705

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 25

ER -