Role of epoxy-fatty acids and epoxide hydrolases in the pathology of neuro-inflammation

Kodani, Sean D.; Morisseau, Christophe

doi:10.1016/j.biochi.2019.01.020

Cited by 42 publications

(33 citation statements)

References 68 publications

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“…Acute inflammation causes localized pain that resolves with the injury, while chronic inflammation can result in organ damages and neuropathic pain that is difficult to treat. Inhibition of sEH has been shown to decrease inflammation as well as the inflammatory and neuropathic pain associated with it in animal models (7)(8)(9)(10). Recent results show that sEH inhibition reduce pain in horses with chronic laminitis (11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

“…While the cyclooxygenase (COX) and lipoxygenase (LOX) branches of the cascade are targets of many pharmaceuticals on the market, including NSAIDs and COXIBs, the CYP450 branch of the cascade has yet to be targeted in the same manner. Within the P450 branch, epoxide metabolites of AA, called epoxy-eicosatrienoic acids (EETs), have anti-inflammatory and analgesic effects (7). However, the endogenous hydrolysis of the EETs to their corresponding diols by soluble epoxide hydrolase (sEH) reduces their biological activity (8).…”

Section: Introductionmentioning

confidence: 99%

“…However, the endogenous hydrolysis of the EETs to their corresponding diols by soluble epoxide hydrolase (sEH) reduces their biological activity (8). Both in vitro and in vivo studies have demonstrated that the modulation of chronic inflammation and neuronal pain by EETs is inversely dependent on the extent of their hydrolysis by sEH (7)(8)(9). Thus, the use of sEH inhibitors to maintain high in vivo levels of EETs is a promising pharmacological approach to treat pain and inflammation (10).…”

Section: Introductionmentioning

confidence: 99%

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Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine

et al. 2020

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The veterinary pharmacopeia available to treat pain and inflammation is limited in number, target of action and efficacy. Inhibitors of soluble epoxide hydrolase (sEH) are a new class of anti-inflammatory, pro-resolving and analgesic drugs being tested in humans that have demonstrated efficacy in laboratory animals. They block the hydrolysis, and thus, increase endogenous concentrations of analgesic and anti-inflammatory signaling molecules called epoxy-fatty acids. Here, we screened a library of 2,300 inhibitors of the sEH human against partially purified feline, canine and equine hepatic sEH to identify inhibitors that are broadly potent among species. Six very potent sEH inhibitors (IC 50 < 1 nM for each enzyme tested) were identified. Their microsomal stability was then measured in hepatic extracts from cat, dog and horse, as well as their solubility in solvents suitable for the formulation of drugs. The trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB, 1,728) appears to be the best compromise between stability and potency across species. Thus, it was selected for further testing in veterinary clinical trials of pain and inflammation in animals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine

et al. 2020

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“…sEH has been shown to be upregulated in a variety of neuropsychiatric conditions with a putative inflammatory component, including major depression, bipolar disorder, and schizophrenia [11]. There is also evidence showing that inhibition of sEH reduces neuronal damage following acute (stroke, hemorrhage) [14] and chronic neurologic insults (Alzheimer's, Parkinson's, and dementia) [41]. sEH is actively pursued both as a biomarker and a drug target in Parkinson's disease, where it tracks with aggregation of α-synuclein and phosphorylated αsynuclein in the striatum [8].…”

Section: Discussionmentioning

confidence: 99%

PET imaging of soluble epoxide hydrolase in non-human primate brain with [18F]FNDP

Minn

Foss

et al. 2020

EJNMMI Res

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Purpose: Soluble 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. [ 18 F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in the baboon brain, radiometabolite analysis, and radiation dosimetry estimate. Methods: Baboon [ 18 F]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 [ 18 F]FNDP in mice and baboons were measured by high-performance liquid chromatography. Regional brain distribution volume (V T) of [ 18 F]FNDP was computed from PET using radiometabolite-corrected arterial input functions. Full body distribution of [ 18 F]FNDP was studied in CD-1 mice, and the human effective dose was estimated using OLINDA/EXM software. Results: [ 18 F]FNDP exhibited high and rapid brain uptake in baboons. AR-9281 blocked [ 18 F]FNDP uptake dose-dependently with a baseline V T of 10.9 ± 2.4 mL/mL and a high-dose blocking V T of 1.0 ± 0.09 mL/mL, indicating substantial binding specificity (91.70 ± 1.74%). The V ND 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 [ 18 F]FNDP enabled an effective dose estimate for humans (0.032 mSv/MBq). [ 18 F]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: [ 18 F]FNDP is a highly sEH-specific radiotracer that is suitable for quantitative PET imaging in the baboon brain. [ 18 F]FNDP holds promise for translation to human subjects.

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“…Role of EETs in neuroinflammation Review [167] Evaluation of antiparkinson activity of PTUPB by measuring dopamine and its metabolites in Drosophila melanogaster: LC-MS/MS method development.…”

Section: Implication Of Seh In Pd Pathologymentioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

et al. 2020

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Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development.

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Role of epoxy-fatty acids and epoxide hydrolases in the pathology of neuro-inflammation

Cited by 42 publications

References 68 publications

Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine

Selection of Potent Inhibitors of Soluble Epoxide Hydrolase for Usage in Veterinary Medicine

PET imaging of soluble epoxide hydrolase in non-human primate brain with [18F]FNDP

Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy

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