The bioactive role of omega-3 endocannabinoid epoxide regioisomers

Lauderdale, Josephine Enales

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https://hdl.handle.net/2142/108554 Copy

Description

Title

The bioactive role of omega-3 endocannabinoid epoxide regioisomers

Author(s)

Lauderdale, Josephine Enales

Issue Date

2020-06-11

Director of Research (if dissertation) or Advisor (if thesis)

Nair, Satish

Doctoral Committee Chair(s)

Nair, Satish

Committee Member(s)

• Gennis, Robert B
• Huang, Raven H
• Fratti, Rutilio A

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• endocannabinoids
• inflammation
• omega-3 fatty acids
• cannabinoid receptors

Abstract

Omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), possess anti-inflammatory properties and are a source for bioactive lipid metabolites. Dietary EPA and DHA are converted to omega-3 endocannabinoids (eCBs), eicosapentaenoicethanolamide (EPEA) and docosahexaenoicethanolamide (DHEA), respectively. Subsequently, omega-3 eCBs are substrates for eicosanoid-synthesizing enzymes, cyclooxygenase, lipoxygenase and cytochrome P450 (CYP450) to generate novel oxygenated lipid mediators. Recently, CYP450 2J2 (CYP2J2) was found to metabolize EPEA to epoxyeicosatetraenoic-ethanolamide (EEQ-EAs) and DHEA to epoxydocosapentaenoic-ethanolamide (EDP-EAs) that are known as omega-3 eCB epoxides. Previously, 17,18-EEQ-EA and 19,20-EDP-EA have shown to have anti-neuroinflammatory, vasodilatory, anti-angiogenic properties, activate cannabinoid receptors and regulate platelet aggregation in vitro. Although these metabolites have demonstrated beneficial results, very few studies have investigated the biological and pharmacological action of the additional regioisomers such as EPEA epoxides, 14,15-EEQ-EA, 11,12-EEQ-EA, 8,9-EEQ-EA and DHEA epoxides, 16,17-EDP-EA, 13,14-EDP-EA, 10,11-EDP-EA and 7,8-EDP-EA. Hence, this dissertation reports the bioactive role of omega-3 eCB epoxide regioisomers generated by CYP450s regarding their anti-inflammatory properties and activation of cannabinoid receptors. We investigated the differential effect of the distinct omega-3 eCB epoxide regioisomers on cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) activation as well as neuroinflammation in BV-2 microglial cells. Our studies indicate that these eCB epoxides activate cannabinoid receptors with distinct receptor selectivity. They also show anti-inflammatory action by reducing nitrite production in lipopolysaccharide (LPS) stimulated BV-2 microglial cells in the presence and absence of soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) inhibitors. Furthermore, we showed that two specific regioisomers 8,9-EEQ-EA and 13,14-EDP-EA, dose dependently reduced nitrite production and reduced levels of interleukin-6 (IL-6) in LPS stimulated BV-2 microglial cells. Lastly, we demonstrated that 8,9-EEQ-EA and 13,14-EDP-EA altered microglial phenotype by reducing proinflammatory mRNA levels of IL-6, inducible nitric oxide synthase (iNOS), tumour necrosis factor α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) as well as increasing anti-inflammatory mRNA levels of arginase-1 (Arg-1) in LPS stimulated BV-2 microglia. Collectively, we showed that omega-3 eCB epoxide regioisomers differentially activate cannabinoid receptors and are anti-neuroinflammatory in microglial cell culture models.

Graduation Semester

2020-08

Type of Resource

Thesis

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http://hdl.handle.net/2142/108554

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Copyright 2020 Josephine Lauderdale

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