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Review
. 2020 Apr:147:106385.
doi: 10.1016/j.prostaglandins.2019.106385. Epub 2019 Nov 5.

Cytochrome P450 derived epoxidized fatty acids as a therapeutic tool against neuroinflammatory diseases

Jogen Atone  1 , Karen Wagner  1 , Kenji Hashimoto  2 , Bruce D Hammock  3
Affiliations
Review

Cytochrome P450 derived epoxidized fatty acids as a therapeutic tool against neuroinflammatory diseases

Jogen Atone et al. Prostaglandins Other Lipid Mediat. 2020 Apr.

Abstract

Cytochrome P450 (CYP) metabolism of arachidonic acid (ARA) produces epoxy fatty acids (EpFAs) such as epoxyeicosatrienoic acids (EETs) that are known to exert protective effects in inflammatory disorders. Endogenous EpFAs are further metabolized into corresponding diols by the soluble epoxide hydrolase (sEH). Through inhibition of sEH, many studies have demonstrated the cardioprotective and renoprotective effects of EpFAs; however, the role of sEH inhibition in modulating the pathogenesis of neuroinflammatory disorders is less well described. In this review, we discuss the current knowledge surrounding the effects of sEH inhibition and EpFA action in neuroinflammatory disorders such as Parkinson's Disease (PD), stroke, depression, epilepsy, and Alzheimer's Disease (AD), as well as the potential mechanisms that underlie the therapeutic effects of sEH inhibition.

Keywords: Alzheimer’s disease (AD); Depression; Epoxyeicosatrienoic acid (EET); Neuroinflammation; Parkinson’s disease (PD); Soluble epoxide hydrolase (sEH); Stroke.

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Conflict of interest statement

Declaration of Competing Interest BD Hammock is a founder and KM Wagner is an employee of EicOsis L.L.C., a startup company advancing sEH inhibitors into the clinic.

Figures

Figure 1.
Figure 1.
Polyunsaturated fatty acids (PUFAs) including arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DHA), can all be metabolized by cytochrome P450 to produce epoxyeicosatrienoic aids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxydocosapentaenoic acids (EDPs), respectively. All regioisomers of these antiinflammatory metabolites can be hydrolyzed by soluble epoxide hydrolase (sEH) into corresponding diols. As such, sEH inhibition can bring about a significant change in the epoxide to diol ratio of DHA and EPA metabolites in addition to ARA derived metabolites. The diols are more polar, more easily excreted, and appear less beneficially active than their corresponding epoxides, and in some cases are pro-inflammatory. These PUFAs may alternatively be metabolized by cyclooxygenase (COX), and lipoxygenase (LOX) independently, or in some cases sequentially.
Figure 2.
Figure 2.
Enzymatic activity of sEH, measured as a rate of [3H] trans-1,3-diphenylpropene oxide (tDPPO) hydrolysis using [3H] tDPPO at a final concentration of 50 μM. Activity was measured in primary rat cortical astrocytes and neurons harvested from neonatal rat pups. The sEH activity of primary neurons were comparable to that of astrocytes, indicating that sEH inhibitors may act directly on rat neurons in addition to glia to prevent neural loss (bars represent ±1 SEM). Two tailed t-test, 10 df, ns.
Figure 3.
Figure 3.
Schematic representation of how epoxyeicosatrienoic acids (EETs) may exert their anti-inflammatory and anti-apoptotic effects. EETs are hypothesized to suppress the activation of NF-κB and ER stress pathways through various means including IKK inhibition and RTK signaling. Increased cAMP could facilitate neural survival through transcription of proteins such as brain derived neurotrophic factor (BDNF), which can amplify through a positive feedback loop, mitigating apoptosis. EETs may also act through regulating ion channels such as CaV1.3 and mitochondrial KATP channels, preventing apoptosis. EET regioisomers have differential affinity for activating various pathways, with cell type and receptor specific effects on inflammation and vasculature remodeling.
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References

    1. Nebert DW, Dalton TP The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6(12) (2006) 947–60. - PubMed
    1. Capdevila JH, Falck JR The CYP P450 arachidonic acid monooxygenases: from cell signaling to blood pressure regulation. Biochem Biophys Res Commun 285(3) (2001) 571–6. - PubMed
    1. Konkel A, Schunck WH Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim Biophys Acta 1814(1) (2011) 210–22. - PubMed
    1. Funk CD Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294(5548) (2001) 1871–5. - PubMed
    1. Nasrallah R, Clark J, Hebert RL Prostaglandins in the kidney: developments since Y2K. Clin Sci (Lond) 113(7) (2007) 297–311. - PubMed

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