Wagner KM

References (19)

Title : Aflatoxin B(1) Increases Soluble Epoxide Hydrolase in the Brain and Induces Neuroinflammation and Dopaminergic Neurotoxicity - Wang_2023_Int.J.Mol.Sci_24_9938
Author(s) : Wang W , Wang Y , Wagner KM , Lee RD , Hwang SH , Morisseau C , Wulff H , Hammock BD
Ref : Int J Mol Sci , 24 :9938 , 2023
Abstract : Parkinson's disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B(1) (AFB(1)), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB(1) leads to neurological disorders as well as cancer. However, whether and how aflatoxin B(1) contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB(1) is shown to induce neuroinflammation, trigger the alpha-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB(1)-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB(1) in vivo and in vitro. Together, our findings suggest a contributing role of AFB(1) to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB(1) exposure.
ESTHER : Wang_2023_Int.J.Mol.Sci_24_9938
PubMedSearch : Wang_2023_Int.J.Mol.Sci_24_9938
PubMedID: 37373086

Title : Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon - Wang_2023_Int.J.Mol.Sci_24_4570
Author(s) : Wang W , Wagner KM , Wang Y , Singh N , Yang J , He Q , Morisseau C , Hammock BD
Ref : Int J Mol Sci , 24 :4570 , 2023
Abstract : Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and beta-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon.
ESTHER : Wang_2023_Int.J.Mol.Sci_24_4570
PubMedSearch : Wang_2023_Int.J.Mol.Sci_24_4570
PubMedID: 36901999

Title : Aflatoxin B(1) exposure disrupts the intestinal immune function via a soluble epoxide hydrolase-mediated manner - Wang_2022_Ecotoxicol.Environ.Saf_249_114417
Author(s) : Wang W , Wang Y , Yang J , Wagner KM , Hwang SH , Cheng J , Singh N , Edwards P , Morisseau C , Zhang G , Panigrahy D , Hammock BD
Ref : Ecotoxicology & Environmental Safety , 249 :114417 , 2022
Abstract : Aflatoxin B(1) (AFB(1)) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB(1) via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB(1) toxicity are still unclear. Here, we showed that AFB(1) disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB(1) immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB(1)-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and alpha-defensin-3 in mice. Altogether, our study demonstrates that AFB(1) exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB(1) global contamination.
ESTHER : Wang_2022_Ecotoxicol.Environ.Saf_249_114417
PubMedSearch : Wang_2022_Ecotoxicol.Environ.Saf_249_114417
PubMedID: 36525946

Title : Soluble epoxide hydrolase inhibition alleviates chemotherapy induced neuropathic pain - Takeshita_2022_Front.Pain.Res.(Lausanne)_3_1100524
Author(s) : Takeshita AA , Hammock BD , Wagner KM
Ref : Front Pain Res (Lausanne) , 3 :1100524 , 2022
Abstract : Chemotherapy induced peripheral neuropathy (CIPN) is a particularly pernicious form of neuropathy and the associated pain is the primary dose-limiting factor of life-prolonging chemotherapy treatment. The prevalence of CIPN is high and can last long after treatment has been stopped. Currently, late in the COVID-19 pandemic, there are still increased psychological pressures on cancer patients as well as additional challenges in providing analgesia for them. These include the risks of nonsteroidal anti-inflammatory drug (NSAID) analgesics potentially masking early infection symptoms and the immunosuppression of steroidal and opiate based approaches. Even without these concerns, CIPN is often inadequately treated with few therapies that offer significant pain relief. The experiments we report use soluble epoxide hydrolase inhibitors (sEHI) which relieved this intractable pain in preclinical models. Doses of EC5026, an IND candidate intended to treat neuropathic pain, elicited dose dependent analgesic responses in multiple models including platinum-based, taxane, and vinca alkaloid-based CIPN pain in Sprague Dawley rats. At the same time as a class, the sEHI are known to result in fewer debilitating side effects of other analgesics, likely due to their novel mechanism of action. Overall, the observed dose-dependent analgesia in both male and female rats across multiple models of chemotherapy induced neuropathic pain holds promise as a useful tool when translated to the clinic.
ESTHER : Takeshita_2022_Front.Pain.Res.(Lausanne)_3_1100524
PubMedSearch : Takeshita_2022_Front.Pain.Res.(Lausanne)_3_1100524
PubMedID: 36700145

Title : Inhibition of the Soluble Epoxide Hydrolase as an Analgesic Strategy: A Review of Preclinical Evidence - Wang_2021_J.Pain.Res_14_61
Author(s) : Wang Y , Wagner KM , Morisseau C , Hammock BD
Ref : J Pain Res , 14 :61 , 2021
Abstract : Chronic pain is a complicated condition which causes substantial physical, emotional, and financial impacts on individuals and society. However, due to high cost, lack of efficacy and safety problems, current treatments are insufficient. There is a clear unmet medical need for safe, nonaddictive and effective therapies in the management of pain. Epoxy-fatty acids (EpFAs), which are natural signaling molecules, play key roles in mediation of both inflammatory and neuropathic pain sensation. However, their molecular mechanisms of action remain largely unknown. Soluble epoxide hydrolase (sEH) rapidly converts EpFAs into less bioactive fatty acid diols in vivo; therefore, inhibition of sEH is an emerging therapeutic target to enhance the beneficial effect of natural EpFAs. In this review, we will discuss sEH inhibition as an analgesic strategy for pain management and the underlying molecular mechanisms.
ESTHER : Wang_2021_J.Pain.Res_14_61
PubMedSearch : Wang_2021_J.Pain.Res_14_61
PubMedID: 33488116

Title : Soluble Epoxide Hydrolase Deletion Limits High-Fat Diet-Induced Inflammation - Wagner_2021_Front.Pharmacol_12_778470
Author(s) : Wagner KM , Yang J , Morisseau C , Hammock BD
Ref : Front Pharmacol , 12 :778470 , 2021
Abstract : The soluble epoxide hydrolase (sEH) enzyme is a major regulator of bioactive lipids. The enzyme is highly expressed in liver and kidney and modulates levels of endogenous epoxy-fatty acids, which have pleiotropic biological effects including limiting inflammation, neuroinflammation, and hypertension. It has been hypothesized that inhibiting sEH has beneficial effects on limiting obesity and metabolic disease as well. There is a body of literature published on these effects, but typically only male subjects have been included. Here, we investigate the role of sEH in both male and female mice and use a global sEH knockout mouse model to compare the effects of diet and diet-induced obesity. The results demonstrate that sEH activity in the liver is modulated by high-fat diets more in male than in female mice. In addition, we characterized the sEH activity in high fat content tissues and demonstrated the influence of diet on levels of bioactive epoxy-fatty acids. The sEH KO animals had generally increased epoxy-fatty acids compared to wild-type mice but gained less body weight on higher-fat diets. Generally, proinflammatory prostaglandins and triglycerides were also lower in livers of sEH KO mice fed HFD. Thus, sEH activity, prostaglandins, and triglycerides increase in male mice on high-fat diet but are all limited by sEH ablation. Additionally, these changes also occur in female mice though at a different magnitude and are also improved by knockout of the sEH enzyme.
ESTHER : Wagner_2021_Front.Pharmacol_12_778470
PubMedSearch : Wagner_2021_Front.Pharmacol_12_778470
PubMedID: 34975481
Gene_locus related to this paper: mouse-hyes

Title : Adrenic Acid-Derived Epoxy Fatty Acids Are Naturally Occurring Lipids and Their Methyl Ester Prodrug Reduces Endoplasmic Reticulum Stress and Inflammatory Pain - Singh_2021_ACS.Omega_6_7165
Author(s) : Singh N , Barnych B , Wagner KM , Wan D , Morisseau C , Hammock BD
Ref : ACS Omega , 6 :7165 , 2021
Abstract : Adrenic acid (AdA, 22:4) is an omega-6 polyunsaturated fatty acid (PUFA), derived from arachidonic acid. Like other PUFAs, it is metabolized by cytochrome P450s to a group of epoxy fatty acids (EpFAs), epoxydocosatrienoic acids (EDTs). EpFAs are lipid mediators with various beneficial bioactivities, including exertion of analgesia and reduction of endoplasmic reticulum (ER) stress, that are degraded to dihydroxy fatty acids by the soluble epoxide hydrolase (sEH). However, the biological characteristics and activities of EDTs are relatively unexplored, and, alongside dihydroxydocosatrienoic acids (DHDTs), they had not been detected in vivo. Herein, EDT and DHDT regioisomers were synthesized, purified, and used as standards for analysis with a selective and quantitative high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Biological verification in AdA-rich tissues suggests that basal metabolite levels are highest in the liver, with 16,17-EDT concentrations consistently being the greatest across the analyzed tissues. Enzyme hydrolysis assessment revealed that EDTs are sEH substrates, with greatest relative rate preference for the 13,14-EDT regioisomer. Pretreatment with an EDT methyl ester regioisomer mixture significantly reduced the onset of tunicamycin-stimulated ER stress in human embryonic kidney cells. Finally, administration of the regioisomeric mixture effectively alleviated carrageenan-induced inflammatory pain in rats. This study indicates that EDTs and DHDTs are naturally occurring lipids, and EDTs could be another therapeutically relevant group of EpFAs.
ESTHER : Singh_2021_ACS.Omega_6_7165
PubMedSearch : Singh_2021_ACS.Omega_6_7165
PubMedID: 33748630

Title : Soluble epoxide hydrolase inhibitor mediated analgesia lacks tolerance in rat models - Wagner_2020_Brain.Res_1728_146573
Author(s) : Wagner KM , Atone J , Hammock BD
Ref : Brain Research , 1728 :146573 , 2020
Abstract : Effectively treating chronic pain remains a therapeutic challenge in the clinic. Recent evidence has shown the inhibition of the soluble epoxide hydrolase (sEH) to be an effective strategy to limit chronic pain in preclinical models, horses and companion animals. Determining the safety of sEH inhibition in addition to this demonstrated efficacy is a critical step to the further development of sEH inhibitors (sEHI) as analgesics. Here we describe a comparison of the sEHI TPPU with other first in class analgesics for human chronic pain. We assess the development of tolerance to the analgesia mediated by TPPU with extended use. We also assess for CNS effects by measuring changes in motor control and functioning. The sEHI are multimodal analgesics that have demonstrated potent efficacy against chronic pain. They have previously been tested and show no reward potential using operant methods. The results of the current experiments show that they lack motor function effects and also lack the development of tolerance with extended dosing.
ESTHER : Wagner_2020_Brain.Res_1728_146573
PubMedSearch : Wagner_2020_Brain.Res_1728_146573
PubMedID: 31790682

Title : N-Benzyl-linoleamide, a Constituent of Lepidium meyenii (Maca), Is an Orally Bioavailable Soluble Epoxide Hydrolase Inhibitor That Alleviates Inflammatory Pain - Singh_2020_J.Nat.Prod_83_3689
Author(s) : Singh N , Barnych B , Morisseau C , Wagner KM , Wan D , Takeshita A , Pham H , Xu T , Dandekar A , Liu JY , Hammock BD
Ref : Journal of Natural Products , 83 :3689 , 2020
Abstract : Lepidium meyenii (maca), a plant indigenous to the Peruvian Andes, recently has been utilized globally for claimed health or recreational benefits. The search for natural products that inhibit soluble epoxide hydrolase (sEH), with therapeutically relevant potencies and concentrations, led to the present study on bioactive amide secondary metabolites found in L. meyenii, the macamides. Based on known and suspected macamides, 19 possible macamides were synthesized and characterized. The majority of these amides displayed excellent inhibitory potency (IC(50) = 20-300 nM) toward the recombinant mouse, rat, and human sEH. Quantitative analysis of commercial maca products revealed that certain products contain known macamides (1-5, 8-12) at therapeutically relevant total concentrations (<=3.29 mg/g of root), while the inhibitory potency of L. meyenii extracts directly correlates with the sum of concentration/IC(50) ratios of macamides present. Considering both its in vitro efficacy and high abundance in commercial products, N-benzyl-linoleamide (4) was identified as a particularly relevant macamide that can be utilized for in vivo studies. Following oral administration in the rat, compound 4 not only displayed acceptable pharmacokinetic characteristics but effectively reduced lipopolysaccharide-induced inflammatory pain. Inhibition of sEH by macamides provides a plausible biological mechanism of action to account for several beneficial effects previously observed with L. meyenii treatments.
ESTHER : Singh_2020_J.Nat.Prod_83_3689
PubMedSearch : Singh_2020_J.Nat.Prod_83_3689
PubMedID: 33320645

Title : Soluble Epoxide Hydrolase Regulation of Lipid Mediators Limits Pain - Wagner_2020_Neurotherapeutics_17_900
Author(s) : Wagner KM , Gomes A , McReynolds CB , Hammock BD
Ref : Neurotherapeutics , 17 :900 , 2020
Abstract : The role of lipids in pain signaling is well established and built on decades of knowledge about the pain and inflammation produced by prostaglandin and leukotriene metabolites of cyclooxygenase and lipoxygenase metabolism, respectively. The analgesic properties of other lipid metabolites are more recently coming to light. Lipid metabolites have been observed to act directly at ion channels and G protein-coupled receptors on nociceptive neurons as well as act indirectly at cellular membranes. Cytochrome P450 metabolism of specifically long-chain fatty acids forms epoxide metabolites, the epoxy-fatty acids (EpFA). The biological role of these metabolites has been found to mediate analgesia in several types of pain pathology. EpFA act through a variety of direct and indirect mechanisms to limit pain and inflammation including nuclear receptor agonism, limiting endoplasmic reticulum stress and blocking mitochondrial dysfunction. Small molecule inhibitors of the soluble epoxide hydrolase can stabilize the EpFA in vivo, and this approach has demonstrated relief in preclinical modeled pain pathology. Moreover, the ability to block neuroinflammation extends the potential benefit of targeting soluble epoxide hydrolase to maintain EpFA for neuroprotection in neurodegenerative disease.
ESTHER : Wagner_2020_Neurotherapeutics_17_900
PubMedSearch : Wagner_2020_Neurotherapeutics_17_900
PubMedID: 32875445

Title : Development of a Highly Sensitive Enzyme-Linked Immunosorbent Assay for Mouse Soluble Epoxide Hydrolase Detection by Combining a Polyclonal Capture Antibody with a Nanobody Tracer - Li_2020_Anal.Chem_92_11654
Author(s) : Li D , Cui Y , Morisseau C , Wagner KM , Cho YS , Hammock BD
Ref : Analytical Chemistry , 92 :11654 , 2020
Abstract : Enzyme-linked immunosorbent assays (ELISA) for the detection of soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of fatty acids and a biomarker, may increasingly represent an important diagnostic tool. However, there is a lack of ELISAs for mouse sEH quantification, thus resulting in a bottleneck in understanding the pathogenesis of many diseases related to sEH based on mouse models. In this work, nanobodies recognizing mouse sEH were obtained through rebiopanning against mouse sEH in the previous phage display library of human sEH. Later, we developed four ELISAs involving a combination of anti-mouse sEH polyclonal antibodies (pAbs) and nanobodies. It was found that the double antibodies worked as dual filters and had a huge impact on both the sensitivity and selectivity of sandwich immunoassays. The switch from anti-human sEH pAbs to anti-mouse sEH pAbs led to over a 100-fold increase in the sensitivity and a dramatic decrease of the limit of detection to a picogram per milliliter range in format B (pAb/biotin-VHH/streptavidin-poly-horseradish peroxidase). Moreover, we found that the four sandwich ELISAs might demonstrate excellent selectivities to mouse sEH, despite the antibodies alone showing significant cross-reactivity to the matrix, indicating the enhanced selectivity of double antibodies as dual filters. Eventually, for the first time, the ELISA (format B) was successfully used to measure the mouse sEH level in cancer cells with ultralow abundances. The ELISAs proposed here represent a sensitive tool for tracking sEH in various biological processes and also provide deep insights into developing sandwich immunoassays against various targets in terms of both the sensitivity and selectivity.
ESTHER : Li_2020_Anal.Chem_92_11654
PubMedSearch : Li_2020_Anal.Chem_92_11654
PubMedID: 32786492

Title : Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity - Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
Author(s) : Hiesinger K , Wagner KM , Hammock BD , Proschak E , Hwang SH
Ref : Prostaglandins Other Lipid Mediat , 140 :31 , 2019
Abstract : Over the last two decades polypharmacology has emerged as a new paradigm in drug discovery, even though developing drugs with high potency and selectivity toward a single biological target is still a major strategy. Often, targeting only a single enzyme or receptor shows lack of efficacy. High levels of inhibitor of a single target also can lead to adverse side effects. A second target may offer additive or synergistic effects to affecting the first target thereby reducing on- and off-target side effects. Therefore, drugs that inhibit multiple targets may offer a great potential for increased efficacy and reduced the adverse effects. In this review we summarize recent findings of rationally designed multitarget compounds that are aimed to improve efficacy and safety profiles compared to those that target a single enzyme or receptor. We focus on dual inhibitors/modulators that target the soluble epoxide hydrolase (sEH) as a common part of their design to take advantage of the beneficial effects of sEH inhibition.
ESTHER : Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
PubMedSearch : Hiesinger_2019_Prostaglandins.Other.Lipid.Mediat_140_31
PubMedID: 30593866

Title : In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea - Wan_2019_Front.Pharmacol_10_464
Author(s) : Wan D , Yang J , McReynolds CB , Barnych B , Wagner KM , Morisseau C , Hwang SH , Sun J , Blocher R , Hammock BD
Ref : Front Pharmacol , 10 :464 , 2019
Abstract : 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU) is a potent soluble epoxide hydrolase (sEH) inhibitor that is used extensively in research for modulating inflammation and protecting against hypertension, neuropathic pain, and neurodegeneration. Despite its wide use in various animal disease models, the metabolism of TPPU has not been well-studied. A broader understanding of its metabolism is critical for determining contributions of metabolites to the overall safety and effectiveness of TPPU. Herein, we describe the identification of TPPU metabolites using LC-MS/MS strategies. Four metabolites of TPPU (M1-M4) were identified from rat urine by a sensitive and specific LC-MS/MS method with double precursor ion scans. Their structures were further supported by LC-MS/MS comparison with synthesized standards. Metabolites M1 and M2 were formed from hydroxylation on a propionyl group of TPPU; M3 was formed by amide hydrolysis of the 1-propionylpiperdinyl group on TPPU; and M4 was formed by further oxidation of the hydroxylated metabolite M2. Interestingly, the predicted alpha-keto amide metabolite and 4-(trifluoromethoxy)aniline (metabolite from urea cleavage) were not detected by the LC-MRM-MS method. This indicates that if formed, the two potential metabolites represent <0.01% of TPPU metabolism. Species differences in the formation of these four identified metabolites was assessed using liver S9 fractions from dog, monkey, rat, mouse, and human. M1, M2, and M3 were generated in liver S9 fractions from all species, and higher amounts of M3 were generated in monkey S9 fractions compared to other species. In addition, rat and human S9 metabolism showed the highest species similarity based on the quantities of each metabolite. The presence of all four metabolites were confirmed in vivo in rats over 72-h post single oral dose of TPPU. Urine and feces were major routes for TPPU excretion. M1, M4 and parent drug were detected as major substances, and M2 and M3 were minor substances. In blood, M1 accounted for ~9.6% of the total TPPU-related exposure, while metabolites M2, M3, and M4 accounted for <0.4%. All four metabolites were potent inhibitors of human sEH but were less potent than the parent TPPU. In conclusion, TPPU is metabolized via oxidation and amide hydrolysis without apparent breakdown of the urea. The aniline metabolites were not observed either in vitro or in vivo. Our findings increase the confidence in the ability to translate preclinical PK of TPPU in rats to humans and facilitates the potential clinical development of TPPU and other sEH inhibitors.
ESTHER : Wan_2019_Front.Pharmacol_10_464
PubMedSearch : Wan_2019_Front.Pharmacol_10_464
PubMedID: 31143115

Title : Orally Available Soluble Epoxide Hydrolase\/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain - Blocher_2018_J.Med.Chem_61_3541
Author(s) : Blocher R , Wagner KM , Gopireddy RR , Harris TR , Wu H , Barnych B , Hwang SH , Xiang YK , Proschak E , Morisseau C , Hammock BD
Ref : Journal of Medicinal Chemistry , 61 :3541 , 2018
Abstract : Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats.
ESTHER : Blocher_2018_J.Med.Chem_61_3541
PubMedSearch : Blocher_2018_J.Med.Chem_61_3541
PubMedID: 29614224

Title : Design and Potency of Dual Soluble Epoxide Hydrolase\/Fatty Acid Amide Hydrolase Inhibitors - Kodani_2018_ACS.Omega_3_14076
Author(s) : Kodani SD , Wan D , Wagner KM , Hwang SH , Morisseau C , Hammock BD
Ref : ACS Omega , 3 :14076 , 2018
Abstract : Fatty acid amide hydrolase (FAAH) is responsible for regulating concentrations of the endocannabinoid arachidonoyl ethanolamide. Multiple FAAH inhibitors have been developed for clinical trials and have failed to demonstrate efficacy at treating pain, despite promising preclinical data. One approach toward increasing the efficacy of FAAH inhibitors is to concurrently inhibit other targets responsible for regulating pain. Here, we designed dual inhibitors targeting the enzymes FAAH and soluble epoxide hydrolase (sEH), which are targets previously shown to synergize at reducing inflammatory and neuropathic pain. Exploration of the sEH/FAAH inhibitor structure-activity relationship started with PF-750, a FAAH inhibitor (IC50 = 19 nM) that weakly inhibited sEH (IC50 = 640 nM). Potency was optimized resulting in an inhibitor with improved potency on both targets (11, sEH IC50 = 5 nM, FAAH IC50 = 8 nM). This inhibitor demonstrated good target selectivity, pharmacokinetic properties (AUC = 1200 h nM, t 1/2 = 4.9 h in mice), and in vivo target engagement.
ESTHER : Kodani_2018_ACS.Omega_3_14076
PubMedSearch : Kodani_2018_ACS.Omega_3_14076
PubMedID: 30411058

Title : Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases - Wagner_2017_Pharmacol.Ther_180_62
Author(s) : Wagner KM , McReynolds CB , Schmidt WK , Hammock BD
Ref : Pharmacol Ther , 180 :62 , 2017
Abstract : 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 EpFAs 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 EpFAs in models of pain and inflammatory diseases.
ESTHER : Wagner_2017_Pharmacol.Ther_180_62
PubMedSearch : Wagner_2017_Pharmacol.Ther_180_62
PubMedID: 28642117

Title : Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress - Ren_2016_Proc.Natl.Acad.Sci.U.S.A_113_E1944
Author(s) : Ren Q , Ma M , Ishima T , Morisseau C , Yang J , Wagner KM , Zhang JC , Yang C , Yao W , Dong C , Han M , Hammock BD , Hashimoto K
Ref : Proc Natl Acad Sci U S A , 113 :E1944 , 2016
Abstract : Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.
ESTHER : Ren_2016_Proc.Natl.Acad.Sci.U.S.A_113_E1944
PubMedSearch : Ren_2016_Proc.Natl.Acad.Sci.U.S.A_113_E1944
PubMedID: 26976569
Gene_locus related to this paper: mouse-hyes

Title : Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy - Lee_2014_J.Med.Chem_57_7016
Author(s) : Lee KS , Liu JY , Wagner KM , Pakhomova S , Dong H , Morisseau C , Fu SH , Yang J , Wang P , Ulu A , Mate CA , Nguyen LV , Hwang SH , Edin ML , Mara AA , Wulff H , Newcomer ME , Zeldin DC , Hammock BD
Ref : Journal of Medicinal Chemistry , 57 :7016 , 2014
Abstract : Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
ESTHER : Lee_2014_J.Med.Chem_57_7016
PubMedSearch : Lee_2014_J.Med.Chem_57_7016
PubMedID: 25079952
Gene_locus related to this paper: human-EPHX2

Title : Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase - Hwang_2011_J.Med.Chem_54_3037
Author(s) : Hwang SH , Wagner KM , Morisseau C , Liu JY , Dong H , Wecksler AT , Hammock BD
Ref : Journal of Medicinal Chemistry , 54 :3037 , 2011
Abstract : A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.
ESTHER : Hwang_2011_J.Med.Chem_54_3037
PubMedSearch : Hwang_2011_J.Med.Chem_54_3037
PubMedID: 21434686