2026-09-20T13:21:24Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/108554 2023-07-11 col_2142_5131 col_2142_14795 com_2142_5130 com_2142_14794 com_2142_14793 com_2142_8903

inflammation omega-3 fatty acids cannabinoid receptors Nair, Satish Nair, Satish Gennis, Robert B Huang, Raven H Fratti, Rutilio A Lauderdale, Josephine Enales 2020-10-07T22:07:08Z 2020-10-07T22:07:08Z 2022-10-07T22:44:53Z 2020-06-11 2020-08 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. Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2022-08-01 The student, Josephine Lauderdale, accepted the attached license on 2020-06-05 at 13:31. The student, Josephine Lauderdale, submitted this Dissertation for approval on 2020-06-05 at 13:32. This Dissertation was approved for publication on 2020-06-11 at 10:32. DSpace SAF Submission Ingestion Package generated from Vireo submission #14927 on 2020-10-02 at 15:30:35 Made available in DSpace on 2020-10-07T22:07:08Z (GMT). No. of bitstreams: 3 LAUDERDALE-DISSERTATION-2020.pdf: 3855764 bytes, checksum: dd2ded3f5fe3d45481a0c65e28eefcfa (MD5) 06052020_Copyright material_permission.docx: 25792 bytes, checksum: fdaa85b98dda83cc1c159e741dc66483 (MD5) LICENSE.txt: 4217 bytes, checksum: a859de2db97413e738ac4e92a3aba377 (MD5) Previous issue date: 2020-06-11 Embargo set by: Seth Robbins for item 116180 Lift date: 2022-10-07T22:07:19Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 116180 Lift date: 2022-10-07T22:44:53Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system U of I Only application/pdf http://hdl.handle.net/2142/108554 en Copyright 2020 Josephine Lauderdale endocannabinoids The bioactive role of omega-3 endocannabinoid epoxide regioisomers text Thesis Biochemistry Biochemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.