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 language | English (US) |
|---|---|
| Pages (from-to) | 1931-1940 |
| Number of pages | 10 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 27 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2007 |
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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
Soluble epoxide hydrolase : A novel therapeutic target in stroke. / Zhang, Wenri; Koerner, Ines; Noppens, Ruediger; Grafe, Marjorie; Tsai, Hsing Ju; Morisseau, Christophe; Luria, Ayala; Hammock, Bruce D.; Falck, John R.; Alkayed, Nabil.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. 12, 12.2007, p. 1931-1940.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Soluble epoxide hydrolase
T2 - A novel therapeutic target in stroke
AU - Zhang, Wenri
AU - Koerner, Ines
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
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
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 -