Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids

Morisseau, Christophe; Inceoglu, Bora; Schmelzer, Kara; Tsai, Hui‐Jen; Jinks, Steven L.; Hegedus, Christine; Hammock, Bruce D.

doi:10.1194/jlr.m006007

Cited by 224 publications

(360 citation statements)

References 47 publications

(87 reference statements)

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“…Although type I diabetes did not elicit major changes in the plasma levels of 13 independent EpFAs, TPAU elevated the levels of these metabolites; the levels of their corresponding dihydroxy metabolites were significantly decreased by sEH inhibition (Table S1). Among those decreased, EpFA metabolites of AA, EPA, and DHA possess direct antinociceptive effects peripherally in a model of inflammatory pain (20). Observed antiallodynic activity corresponded well to enhanced plasma epoxide/diol ratio.…”

Section: Discussionmentioning

confidence: 91%

“…Clearly, these components are present in both the CNS and the peripheral nervous system. Even though the EpFAs do not fulfill the criteria of being neurotransmitters, nor are they known ligands for major ion channels, they strongly regulate nociceptive signaling peripherally, in the spinal cord, and possibly in the brain (20,22). In this study we characterized the acute effect of inhibiting sEH on type I diabetes-induced mechanical allodynia, which was largely effective in eliminating pain behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Table S1 displays the identity and detected quantity of the metabolites analyzed from plasma. it is reasonable that a portion of the observed antinociception is mediated through peripheral mechanisms (20). The mode of action of EpFAs and sEHI in the diabetic neuropathic pain model does not seem to involve their ability to modulate NFĸB and the ensuing down-regulation of COX1/2 because no changes in plasma levels of PGE 2 and PGD 2 are observed (25).…”

Section: Discussionmentioning

confidence: 99%

“…EpFAs are produced from parent linoleic (LA), arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids by multiple isozymes of the cytochrome P450 enzymes (18). These molecules not only have selective and direct antinociceptive effects but also modulate the AA cascade, a major biological pathway (16,19,20). The EpFAs participate in physiological events, such as setting of the vascular tone, and they seem to have more important functions in pathophysiological processes (21)(22)(23).…”

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confidence: 99%

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

Inceoglu

Wagner

Yang

et al. 2012

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

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The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. The progressive damage to the peripheral nervous system is irreversible although strict control of hyperglycemia may prevent further damage. Current treatments include tricyclic antidepressants, anticonvulsants, and opioids, depending on the severity of the pain state. However, available therapeutics have drawbacks, arguing for the need to better understand the pathophysiology of neuropathic pain and develop novel treatments. Here we demonstrate that stabilization of a class of bioactive lipids, epoxygenated fatty acids (EpFAs), greatly reduces allodynia in rats caused by streptozocin-induced type I diabetes. Inhibitors of the soluble epoxide hydrolase (sEHI) elevated and stabilized the levels of plasma and spinal EpFAs, respectively, and generated dose-dependent antiallodynic effects more potently and efficaciously than gabapentin. In acute experiments, positive modulation of EpFAs did not display differences in insulin sensitivity, glucose tolerance, or insulin secretion, indicating the efficacy of sEHIs are not related to the glycemic status. Quantitative metabolomic analysis of a panel of 26 bioactive lipids demonstrated that sEHI-mediated antiallodynic effects coincided with a selective elevation of the levels of EpFAs in the plasma, and a decrease in degradation products coincided with the dihydroxy fatty acids in the spinal cord. Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain.analgesic drug | soluble epoxide hydrolase inhibitor | cytochrome P450 | glucose homeostasis | motor depressant

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Inceoglu

Wagner

Yang

et al. 2012

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

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“…DHA, which is the most abundant omega-3 fatty acid in most tissues (17,18), can efficiently compete with ARA for the metabolism by CYP epoxygenases, leading to replacement of EETs with EDPs in vivo (16,19,20). EETs and EDPs have been investigated as autocrine and paracrine mediators to regulate inflammation and vascular tone (21)(22)(23)(24). In comparison, EDPs have been reported to have more potency on vasodilation and antiinflammation than EETs (22,24).…”

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confidence: 99%

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Zhang

Panigrahy

Mahakian³

et al. 2013

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

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Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGFand fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg·kg −1 ·d −1 ) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ∼70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.

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Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

Gowler

Turnbull

Shahtaheri

et al. 2022

Arthritis & Rheumatology

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Objective Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods Potential associations of chronic knee pain with single‐nucleotide polymorphisms (SNPs) in the gene‐encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N‐[1‐(1‐oxopropy)‐4‐piperidinyl]‐N′‐(trifluoromethoxy)phenyl]‐urea (TPPU) on weight‐bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs. Results In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9‐DHET and 14,15‐DHET. EET levels were unchanged by TPPU administration. Conclusion Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.

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Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids

Cited by 224 publications

References 47 publications

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

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

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

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