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Distribution and expression of soluble epoxide hydrolase in human brain.

ABSTRACT: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid, which function in the brain to regulate cerebral blood flow and protect against ischemic brain injury. EETs are converted by soluble epoxide hydrolase (sEH) to the corresponding inactive diol metabolites. Previous animal studies have indicated that sEH gene deletion or treatment with sEH inhibitors results in increased levels of EETs and protection against stroke-induced brain damage. To begin elucidating the underlying mechanism for these effects, we sought to determine the distribution, expression, and activity of sEH in human brain samples obtained from patients with no neurological changes/pathologies. Immunohistochemical analyses showed the distribution of sEH mainly in the neuronal cell bodies, oligodendrocytes, and scattered astrocytes. Surprisingly, in the choroid plexus, sEH was found to be highly expressed in ependymal cells. Vascular localization of sEH was evident in several regions, where it was highly expressed in the smooth muscles of the arterioles. Western blot analysis and enzyme assays confirmed the presence of sEH in the normal brain. Our results indicate differential localization of sEH in the human brain, thus suggestive of an essential role for this enzyme in the central nervous system. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

SUBMITTER: Sura P

PROVIDER: S-EPMC2386770 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Distribution and expression of soluble epoxide hydrolase in human brain.

Sura Priyanka P Sura Radhakrishna R Enayetallah Ahmed E AE Grant David F DF

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20080303 6

Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid, which function in the brain to regulate cerebral blood flow and protect against ischemic brain injury. EETs are converted by soluble epoxide hydrolase (sEH) to the corresponding inactive diol metabolites. Previous animal studies have indicated that sEH gene deletion or treatment with sEH inhibitors results in increased levels of EETs and protection against stroke-induced brain damage. To begin elucidating the u ...[more]

PMID: 18319271

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Project description:PurposeSoluble epoxide hydrolase (sEH) is a promising candidate positron emission tomography (PET) imaging biomarker altered in various disorders, including vascular cognitive impairment (VCI), Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, known to regulate levels of epoxyeicosatrienoic acids (EETs) and play an important role in neurovascular coupling. [18F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in the baboon brain, radiometabolite analysis, and radiation dosimetry estimate.MethodsBaboon [18F]FNDP dynamic PET studies were performed at baseline and with blocking doses of the selective sEH inhibitor AR-9281 to evaluate sEH binding specificity. Radiometabolites of [18F]FNDP in mice and baboons were measured by high-performance liquid chromatography. Regional brain distribution volume (VT) of [18F]FNDP was computed from PET using radiometabolite-corrected arterial input functions. Full body distribution of [18F]FNDP was studied in CD-1 mice, and the human effective dose was estimated using OLINDA/EXM software.Results[18F]FNDP exhibited high and rapid brain uptake in baboons. AR-9281 blocked [18F]FNDP uptake dose-dependently with a baseline VT of 10.9 ± 2.4 mL/mL and a high-dose blocking VT of 1.0 ± 0.09 mL/mL, indicating substantial binding specificity (91.70 ± 1.74%). The VND was estimated as 0.865 ± 0.066 mL/mL. The estimated occupancy values of AR-9281 were 99.2 ± 1.1% for 1 mg/kg, 88.6 ± 1.3% for 0.1 mg/kg, and 33.8 ± 3.8% for 0.02 mg/kg. Murine biodistribution of [18F]FNDP enabled an effective dose estimate for humans (0.032 mSv/MBq). [18F]FNDP forms hydrophilic radiometabolites in murine and non-human primate plasma. However, only minute amounts of the radiometabolites entered the animal brain (< 2% in mice).Conclusions[18F]FNDP is a highly sEH-specific radiotracer that is suitable for quantitative PET imaging in the baboon brain. [18F]FNDP holds promise for translation to human subjects.

Dataset Information

Distribution and expression of soluble epoxide hydrolase in human brain.

Publications

Distribution and expression of soluble epoxide hydrolase in human brain.

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