Soluble epoxide hydrolase activity regulates inflammatory responses and seizure generation in two mouse models of temporal lobe epilepsy

Hung, Yu-Min; Hung, Szu Chun; Wu, Yichen; Wong, Lin-King; Lai, Ming-Tsong; Shih, Yang-Hsin; Lee, Tzong‐Shyuan; Lin, Yung-Yang

doi:10.1016/j.bbi.2014.07.016

Cited by 47 publications

(38 citation statements)

References 62 publications

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“…Furthermore, sEHI are efficacious in both chemical and electrical models of temporal lobe epilepsy. In pilocarpine induced status epilepticus (SE), sEHI increased EETs and EET/DHET ratios, reduced neuroinflammation, as well as seizure frequency and duration (Hung, et al, 2015). In the same study, sEHI increased seizure-induction thresholds in epileptogenesis induced by electrical basolateral amygdala (BLA) kindling.…”

Section: Seh As a Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Wagner

McReynolds

Schmidt

et al. 2017

Pharmacology & Therapeutics

225

204

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Eicosanoids are biologically active lipid signaling molecules derived from polyunsaturated fatty acids. Many of the actions of eicosanoid metabolites formed by cyclooxygenase and lipoxygenase enzymes have been characterized, however, the epoxy-fatty acids (EpFAs) formed by cytochrome P450 enzymes are newly described by comparison. The EpFA metabolites modulate a diverse set of physiologic functions that include inflammation and nociception among others. Regulation of EpFAs occurs primarily via release, biosynthesis and enzymatic transformation by the soluble epoxide hydrolase (sEH). Targeting sEH with small molecule inhibitors has enabled observation of the biological activity of the EpFAs in vivo in animal models, greatly contributing to the overall understanding of their role in the inflammatory response. Their role in modulating inflammation has been demonstrated in disease models including cardiovascular pathology and inflammatory pain, but extends to neuroinflammation and neuroinflammatory disease. Moreover, while the EpFA demonstrate activity against inflammatory pain, interestingly, this action extends to blocking chronic neuropathic pain as well. This review outlines the role of modulating sEH and the biological action of EpFA in models of pain and inflammatory diseases.

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Section: Seh As a Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Wagner

McReynolds

Schmidt

et al. 2017

Pharmacology & Therapeutics

225

204

View full text Add to dashboard Cite

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“…Patients with the common K55R genetic polymorphism in the sEH gene ( Ephx2 ) demonstrated 30% lower levels of EETs due to increased activity of sEH (12) and they exhibited a mortality of 28.6% after stroke versus 5.3% in the control subjects (11). Other studies have demonstrated highly increased expression of sEH in animal models of epilepsy (13) and Parkinson’s disease (14). …”

Section: Introductionmentioning

confidence: 98%

¹⁸F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

et al. 2016

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Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which have vasoactive and anti-inflammatory properties. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and non-human primate brain with PET. Methods 18F-FNDP was synthesized from the corresponding bromo-precursor. sEH inhibitory activity of 18F-FNDP was measured using the sEH Inhibitor Screening Assay Kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pre-treatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in three baboons with regional tracer binding quantified using distribution volume (VT). Metabolism of 18F-FNDP in baboon was assessed using high performance liquid chromatography. Results 18F-FNDP (Ki = 1.73 nM) was prepared in one step in radiochemical yield of 14 ± 7%, specific radioactivity in the range of 888 – 3,774 GBq/µmol and in radiochemical purity > 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2 percent injected dose per gram of tissue at peak uptake. Blockade of 80–90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH-KO mice. PET baboon brain distribution paralleled that seen in mouse with marked blockade (95%) noted in all regions indicating sEH-mediated uptake of 18F-FNDP. Two hydrophilic metabolites were identified with 20% parent compound present at 90 min post-injection in baboon plasma. Conclusion 18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and non-human primate brain specifically. 18F-FNDP is a promising PET radiotracer likely to be useful for understanding the role of sEH in a variety of conditions affecting the central nervous system.

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“…Thus, some confidence in ultimate clinical success with sEH inhibitors to treat pain comes from pain reduction in five different animal orders. In addition to pain, several studies suggest that sEH inhibitors could be broadly effective in a variety of diseases involving neuroinflammation (Hung et al, 2015).…”

Section: Developing a Path To The Clinicmentioning

confidence: 99%

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

Kodani¹,

Hammock²

2015

Drug Metab Dispos

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Dr. Bernard Brodie's legacy is built on fundamental discoveries in pharmacology and drug metabolism that were then translated to the clinic to improve patient care. Similarly, the development of a novel class of therapeutics termed the soluble epoxide hydrolase (sEH) inhibitors was originally spurred by fundamental research exploring the biochemistry and physiology of the sEH. Here, we present an overview of the history and current state of research on epoxide hydrolases, specifically focusing on sEHs. In doing so, we start with the translational project studying the metabolism of the insect juvenile hormone mimic R-20458 [(E)-6,7-epoxy-1-(4-ethylphenoxy)-3,7-dimethyl-2-octene], which led to the identification of the mammalian sEH. Further investigation of this enzyme and its substrates, including the epoxyeicosatrienoic acids, led to insight into mechanisms of inflammation, chronic and neuropathic pain, angiogenesis, and other physiologic processes. This basic knowledge in turn led to the development of potent inhibitors of the sEH that are promising therapeutics for pain, hypertension, chronic obstructive pulmonary disorder, arthritis, and other disorders.

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Soluble epoxide hydrolase activity regulates inflammatory responses and seizure generation in two mouse models of temporal lobe epilepsy

Cited by 47 publications

References 62 publications

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

¹⁸F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

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Soluble epoxide hydrolase activity regulates inflammatory responses and seizure generation in two mouse models of temporal lobe epilepsy

Cited by 47 publications

References 62 publications

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

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¹⁸F-FNDP for PET Imaging of Soluble Epoxide Hydrolase