Soluble epoxide hydrolase: A novel therapeutic target in stroke

Wenri Zhang, Ines P. Koerner, Ruediger Noppens, Marjorie Grafe, Hsing Ju Tsai, Christophe Morisseau, Ayala Luria, Bruce D. Hammock, John R. Falck, Nabil J. Alkayed

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.

Original languageEnglish (US)
Pages (from-to)1931-1940
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number12
DOIs
StatePublished - Dec 2007

Fingerprint

Epoxide Hydrolases
lauric acid
Stroke
Cerebrovascular Circulation
Esters
Brain
Eicosanoids
Middle Cerebral Artery Infarction
Therapeutics
Intraperitoneal Injections
Acids
Vascular System Injuries
Regional Blood Flow
Autoradiography
Reperfusion
Blood Vessels
Ischemia
Wounds and Injuries

Keywords

  • CBF
  • Cerebral ischemia
  • EETs
  • Eicosanoids
  • EPHX2
  • Neuroprotection
  • P450 epoxygenase
  • sEH
  • Stroke

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

Zhang, W., Koerner, I. P., Noppens, R., Grafe, M., Tsai, H. J., Morisseau, C., ... Alkayed, N. J. (2007). Soluble epoxide hydrolase: A novel therapeutic target in stroke. Journal of Cerebral Blood Flow and Metabolism, 27(12), 1931-1940. https://doi.org/10.1038/sj.jcbfm.9600494

Soluble epoxide hydrolase : A novel therapeutic target in stroke. / Zhang, Wenri; Koerner, Ines P.; Noppens, Ruediger; Grafe, Marjorie; Tsai, Hsing Ju; Morisseau, Christophe; Luria, Ayala; Hammock, Bruce D.; Falck, John R.; Alkayed, Nabil J.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. 12, 12.2007, p. 1931-1940.

Research output: Contribution to journalArticle

Zhang, W, Koerner, IP, Noppens, R, Grafe, M, Tsai, HJ, Morisseau, C, Luria, A, Hammock, BD, Falck, JR & Alkayed, NJ 2007, 'Soluble epoxide hydrolase: A novel therapeutic target in stroke', Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 12, pp. 1931-1940. https://doi.org/10.1038/sj.jcbfm.9600494
Zhang W, Koerner IP, Noppens R, Grafe M, Tsai HJ, Morisseau C et al. Soluble epoxide hydrolase: A novel therapeutic target in stroke. Journal of Cerebral Blood Flow and Metabolism. 2007 Dec;27(12):1931-1940. https://doi.org/10.1038/sj.jcbfm.9600494
Zhang, Wenri ; Koerner, Ines P. ; Noppens, Ruediger ; Grafe, Marjorie ; Tsai, Hsing Ju ; Morisseau, Christophe ; Luria, Ayala ; Hammock, Bruce D. ; Falck, John R. ; Alkayed, Nabil J. / Soluble epoxide hydrolase : A novel therapeutic target in stroke. In: Journal of Cerebral Blood Flow and Metabolism. 2007 ; Vol. 27, No. 12. pp. 1931-1940.
@article{476a2ef4a8e94bfea34c6df2df70c37a,
title = "Soluble epoxide hydrolase: A novel therapeutic target in stroke",
abstract = "The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.",
keywords = "CBF, Cerebral ischemia, EETs, Eicosanoids, EPHX2, Neuroprotection, P450 epoxygenase, sEH, Stroke",
author = "Wenri Zhang and Koerner, {Ines P.} and Ruediger Noppens and Marjorie Grafe and Tsai, {Hsing Ju} and Christophe Morisseau and Ayala Luria and Hammock, {Bruce D.} and Falck, {John R.} and Alkayed, {Nabil J.}",
year = "2007",
month = "12",
doi = "10.1038/sj.jcbfm.9600494",
language = "English (US)",
volume = "27",
pages = "1931--1940",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Soluble epoxide hydrolase

T2 - A novel therapeutic target in stroke

AU - Zhang, Wenri

AU - Koerner, Ines P.

AU - Noppens, Ruediger

AU - Grafe, Marjorie

AU - Tsai, Hsing Ju

AU - Morisseau, Christophe

AU - Luria, Ayala

AU - Hammock, Bruce D.

AU - Falck, John R.

AU - Alkayed, Nabil J.

PY - 2007/12

Y1 - 2007/12

N2 - The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.

AB - The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.

KW - CBF

KW - Cerebral ischemia

KW - EETs

KW - Eicosanoids

KW - EPHX2

KW - Neuroprotection

KW - P450 epoxygenase

KW - sEH

KW - Stroke

UR - http://www.scopus.com/inward/record.url?scp=34347407952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34347407952&partnerID=8YFLogxK

U2 - 10.1038/sj.jcbfm.9600494

DO - 10.1038/sj.jcbfm.9600494

M3 - Article

C2 - 17440491

AN - SCOPUS:34347407952

VL - 27

SP - 1931

EP - 1940

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 12

ER -