Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Inceoglu, Bora; Wagner, Karen; Yang, Jun; Bettaieb, Ahmed; Schebb, Nils Helge; Hwang, Sung Hee; Morisseau, Christophe; Haj, Fawaz G.; Hammock, Bruce D.

doi:10.1073/pnas.1208708109

Cited by 72 publications

(85 citation statements)

References 40 publications

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“…Increasing the levels of EpFAs by inhibiting the enzyme sEH effectively blocks ER stress in the liver and adipose tissue of mice fed a high fat diet (20). In addition, sEH inhibitors are strong analgesics, and specifically in diabetic rats, they eliminate pain-related behavior in a dose dependent manner (10). Blood levels of sEH inhibitor, changes in epoxy fatty acids and antinociceptive activity triangulate to full target engagement.…”

Section: Resultsmentioning

confidence: 99%

“…While studying EpFAs and sEH enzyme, we reported its upregulation in the nervous system of diabetic rodents (10). Similarly sEH expression is elevated in heart, liver and adipose tissue arguing for a global increase in response to diabetes (11)(12)(13).…”

mentioning

confidence: 99%

“…These lipids, also termed epoxy fatty acids (EpFAs), are analgesic, anticonvulsant and antiinflammatory (14)(15)(16)(17)(18). When EpFAs are stabilized by inhibiting sEH in diabetic animals, neuropathic pain is effectively blocked (10,18). A large number of biological effects have been attributed to EpFAs (19).…”

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confidence: 99%

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Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Inceoglu

Bettaieb

Trindade‐da‐Silva

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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153

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Despite intensive effort and resulting gains in understanding the mechanisms underlying neuropathic pain, limited success in therapeutic approaches have been attained. A recently identified, nonchannel, nonneurotransmitter therapeutic target for pain is the enzyme soluble epoxide hydrolase (sEH). The sEH degrades natural analgesic lipid mediators, epoxy fatty acids (EpFAs), therefore its inhibition stabilizes these bioactive mediators. Here we demonstrate the effects of EpFAs on diabetes induced neuropathic pain and define a previously unknown mechanism of pain, regulated by endoplasmic reticulum (ER) stress. The activation of ER stress is first quantified in the peripheral nervous system of type I diabetic rats. We demonstrate that both pain and markers of ER stress are reversed by a chemical chaperone. Next, we identify the EpFAs as upstream modulators of ER stress pathways. Chemical inducers of ER stress invariably lead to pain behavior that is reversed by a chemical chaperone and an inhibitor of sEH. The rapid occurrence of pain behavior with inducers, equally rapid reversal by blockers and natural incidence of ER stress in diabetic peripheral nervous system (PNS) argue for a major role of the ER stress pathways in regulating the excitability of the nociceptive system. Understanding the role of ER stress in generation and maintenance of pain opens routes to exploit this system for therapeutic purposes.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Inceoglu

Bettaieb

Trindade‐da‐Silva

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

153

168

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“…8A) . Unexpectedly, other forms of pain that are not inflammation based, such as traumatic nerve injury or diabetic neuropathic pain, have also been prevented by sEH inhibition (Inceoglu et al, 2012). Neuropathic pain has been traditionally difficult to treat because of the low efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) and undesirable side effects of other therapies including morphine and gabapentin (Inceoglu et al, 2012).…”

Section: Discovering Physiologic Roles For Epfasmentioning

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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“…Using potent inhibitors of sEH to stabilize endogenous EETs (14)(15)(16)(17), sEH has been recently demonstrated in animal models as a novel therapeutic target (4) for treating cardiovascular diseases (18)(19)(20), inflammation (21,22), pain (23)(24)(25), and pulmonary diseases such as pulmonary hypertension (26,27) and tobacco smoke-induced chronic obstructive pulmonary disease (9,10).…”

Section: Clinical Relevancementioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

Yang¹,

Bratt

Franzi

et al. 2015

Am J Respir Cell Mol Biol

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Control of airway inflammation is critical in asthma treatment. Soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. We hypothesized that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. BALB/c mice were sensitized and exposed to OVA over 6 weeks. A sEH inhibitor (sEHI) was administered for 2 weeks. Respiratory system compliance, resistance, and forced exhaled nitric oxide were measured. Lung lavage cell counts were performed, and selected cytokines and chemokines in the lung lavage fluid were measured. A LC/MS/MS method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. The pharmacological inhibition of sEH increased concentrations of the antiinflammatory epoxy eicosatrienoic acids and simultaneously decreased the concentrations of the proinflammatory dihydroxyeicosatrienoic acids and dihydroxyoctadecenoic acids. All monitored inflammatory markers, including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVA-exposed mice were reduced by sEHI. The type 2 T helper cell (Th2) cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after sEHI administration. Resistance and dynamic lung compliance were also improved by sEHI. We demonstrated that sEHI administration attenuates allergic airway inflammation and airway responsiveness in a murine model. sEHI may have potential as a novel therapeutic strategy for allergic asthma.Keywords: soluble epoxide hydrolase; asthma; inflammation; lipid mediators; type 2 T helper cell cytokines Clinical RelevanceWe demonstrated that inhibition of soluble epoxide hydrolase attenuates allergic airway inflammation and airway responsiveness in a murine model. Therefore, sEH inhibitors may have potential as a novel therapeutic strategy for allergic asthma.Three hundred million people worldwide suffer from episodic or persistent asthma (1). The cornerstones of treatment for persistent asthma are inhaled corticosteroids and b-agonist bronchodilators; however, a significant minority of patients with asthma does not respond well to these therapies (2). Thus, there are ongoing efforts to develop novel treatment strategies (3), such as specific antagonists of type 2 T helper cell (Th2) cytokines and mediators.

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Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes

Cited by 72 publications

References 40 publications

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

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

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

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