Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)- cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke

Jafar Sadik B Shaik, Muzamil Ahmad, Wenjin Li, Marie E. Rose, Lesley M. Foley, T. Kevin Hitchens, Steven H. Graham, Sung Hee Hwang, Bruce D. Hammock, Samuel M. Poloyac

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Soluble epoxide hydrolase (sEH) diminishes vasodilatory and neuroprotective effects of epoxyeicosatrienoic acids by hydrolyzing them to inactive dihydroxy metabolites. The primary goals of this study were to investigate the effects of acute sEH inhibition by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on infarct volume, functional outcome, and changes in cerebral blood flow (CBF) in a rat model of ischemic stroke. Focal cerebral ischemia was induced in rats for 90 min followed by reperfusion. At the end of 24 h after reperfusion rats were euthanized for infarct volume assessment by triphenyltetrazolium chloride staining. Brain cortical sEH activity was assessed by ultra performance liquid chromatography-tandem mass spectrometry. Functional outcome at 24 and 48 h after reperfusion was evaluated by arm flexion and sticky-tape tests. Changes in CBF were assessed by arterial spin-labeled-MRI at baseline, during ischemia, and at 180 min after reperfusion. Neuroprotective effects of t-AUCB were evaluated in primary rat neuronal cultures by Cytotox-Flour kit and propidium iodide staining. t-AUCB significantly reduced cortical infarct volume by 35% (14.5 ± 2.7% vs. 41.5 ± 4.5%), elevated cumulative epoxyeicosatrienoic acids-to-dihydroxyeicosatrienoic acids ratio in brain cortex by twofold (4.40 ± 1.89 vs. 1.97 ± 0.85), and improved functional outcome in arm-flexion test (day 1: 3.28 ± 0.5 s vs. 7.50 ± 0.9 s; day 2: 1.71 ± 0.4 s vs. 5.28 ± 0.5 s) when compared with that of the vehicle-treated group. t-AUCB significantly reduced neuronal cell death in a dose-dependent manner (vehicle: 70.9 ± 7.1% vs. t-AUCB0.1μM: 58 ± 5.11% vs. t-AUCB0.5μM: 39.9 ± 5.8%). These findings suggest that t-AUCB may exert its neuroprotective effects by affecting multiple components of neurovascular unit including neurons, astrocytes, and microvascular flow.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number11
DOIs
StatePublished - Dec 1 2013

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Epoxide Hydrolases
Benzoic Acid
Stroke
Reperfusion
Cerebrovascular Circulation
Neuroprotective Agents
Acids
Staining and Labeling
Propidium
Brain
Flour
Tandem Mass Spectrometry
Brain Ischemia
Liquid Chromatography
Astrocytes
Cell Death
Ischemia
4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
Neurons

Keywords

  • Arachidonic acid
  • Cerebral blood flow
  • Cytochrome P-450
  • Ischemic stroke
  • Middle cerebral artery occlusion

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)- cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke. / Shaik, Jafar Sadik B; Ahmad, Muzamil; Li, Wenjin; Rose, Marie E.; Foley, Lesley M.; Kevin Hitchens, T.; Graham, Steven H.; Hwang, Sung Hee; Hammock, Bruce D.; Poloyac, Samuel M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 11, 01.12.2013.

Research output: Contribution to journalArticle

Shaik, Jafar Sadik B ; Ahmad, Muzamil ; Li, Wenjin ; Rose, Marie E. ; Foley, Lesley M. ; Kevin Hitchens, T. ; Graham, Steven H. ; Hwang, Sung Hee ; Hammock, Bruce D. ; Poloyac, Samuel M. / Soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)- cyclohexyloxy]-benzoic acid is neuroprotective in rat model of ischemic stroke. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 305, No. 11.
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abstract = "Soluble epoxide hydrolase (sEH) diminishes vasodilatory and neuroprotective effects of epoxyeicosatrienoic acids by hydrolyzing them to inactive dihydroxy metabolites. The primary goals of this study were to investigate the effects of acute sEH inhibition by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on infarct volume, functional outcome, and changes in cerebral blood flow (CBF) in a rat model of ischemic stroke. Focal cerebral ischemia was induced in rats for 90 min followed by reperfusion. At the end of 24 h after reperfusion rats were euthanized for infarct volume assessment by triphenyltetrazolium chloride staining. Brain cortical sEH activity was assessed by ultra performance liquid chromatography-tandem mass spectrometry. Functional outcome at 24 and 48 h after reperfusion was evaluated by arm flexion and sticky-tape tests. Changes in CBF were assessed by arterial spin-labeled-MRI at baseline, during ischemia, and at 180 min after reperfusion. Neuroprotective effects of t-AUCB were evaluated in primary rat neuronal cultures by Cytotox-Flour kit and propidium iodide staining. t-AUCB significantly reduced cortical infarct volume by 35{\%} (14.5 ± 2.7{\%} vs. 41.5 ± 4.5{\%}), elevated cumulative epoxyeicosatrienoic acids-to-dihydroxyeicosatrienoic acids ratio in brain cortex by twofold (4.40 ± 1.89 vs. 1.97 ± 0.85), and improved functional outcome in arm-flexion test (day 1: 3.28 ± 0.5 s vs. 7.50 ± 0.9 s; day 2: 1.71 ± 0.4 s vs. 5.28 ± 0.5 s) when compared with that of the vehicle-treated group. t-AUCB significantly reduced neuronal cell death in a dose-dependent manner (vehicle: 70.9 ± 7.1{\%} vs. t-AUCB0.1μM: 58 ± 5.11{\%} vs. t-AUCB0.5μM: 39.9 ± 5.8{\%}). These findings suggest that t-AUCB may exert its neuroprotective effects by affecting multiple components of neurovascular unit including neurons, astrocytes, and microvascular flow.",
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AU - Ahmad, Muzamil

AU - Li, Wenjin

AU - Rose, Marie E.

AU - Foley, Lesley M.

AU - Kevin Hitchens, T.

AU - Graham, Steven H.

AU - Hwang, Sung Hee

AU - Hammock, Bruce D.

AU - Poloyac, Samuel M.

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N2 - Soluble epoxide hydrolase (sEH) diminishes vasodilatory and neuroprotective effects of epoxyeicosatrienoic acids by hydrolyzing them to inactive dihydroxy metabolites. The primary goals of this study were to investigate the effects of acute sEH inhibition by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) on infarct volume, functional outcome, and changes in cerebral blood flow (CBF) in a rat model of ischemic stroke. Focal cerebral ischemia was induced in rats for 90 min followed by reperfusion. At the end of 24 h after reperfusion rats were euthanized for infarct volume assessment by triphenyltetrazolium chloride staining. Brain cortical sEH activity was assessed by ultra performance liquid chromatography-tandem mass spectrometry. Functional outcome at 24 and 48 h after reperfusion was evaluated by arm flexion and sticky-tape tests. Changes in CBF were assessed by arterial spin-labeled-MRI at baseline, during ischemia, and at 180 min after reperfusion. Neuroprotective effects of t-AUCB were evaluated in primary rat neuronal cultures by Cytotox-Flour kit and propidium iodide staining. t-AUCB significantly reduced cortical infarct volume by 35% (14.5 ± 2.7% vs. 41.5 ± 4.5%), elevated cumulative epoxyeicosatrienoic acids-to-dihydroxyeicosatrienoic acids ratio in brain cortex by twofold (4.40 ± 1.89 vs. 1.97 ± 0.85), and improved functional outcome in arm-flexion test (day 1: 3.28 ± 0.5 s vs. 7.50 ± 0.9 s; day 2: 1.71 ± 0.4 s vs. 5.28 ± 0.5 s) when compared with that of the vehicle-treated group. t-AUCB significantly reduced neuronal cell death in a dose-dependent manner (vehicle: 70.9 ± 7.1% vs. t-AUCB0.1μM: 58 ± 5.11% vs. t-AUCB0.5μM: 39.9 ± 5.8%). These findings suggest that t-AUCB may exert its neuroprotective effects by affecting multiple components of neurovascular unit including neurons, astrocytes, and microvascular flow.

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KW - Arachidonic acid

KW - Cerebral blood flow

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KW - Ischemic stroke

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