Effect of the Lipid Peroxidation Product 4-Hydroxynonenal on Neuroinflammation in Microglial Cells: Protective Role of Quercetin and Monochloropivaloylquercetin

• Published in: Turkish journal of pharmaceutical sciences Vol. 16; no. 1; pp. 54 - 61
• Main Authors: Cumaoğlu, Ahmet, Ağkaya, Aslı Özge, Özkul, Zehra
• Format: Journal Article
• Language: English
• Published: Turkey Türk Eczacılar Birliği 01.03.2019; Galenos Publishing House; Galenos Publishing
• Subjects: Antioxidants; Arthritis; Bioavailability; Cytokines; Eczacılık; Gene expression; Inflammation; Lipid peroxidation; Lipids; Original; Oxidative stress; Physiology; Proteins; Sağlık Hizmetleri; Tıp; Ankara; Türkiye; United States > US; hemeoxygenase-1; quercetin; 4-Hydroxynonenal; inflammation; microglia; cyclooxygenase-2; kersetin; 4-Hidroksinonenal; siklooksijenaz-2; hemoksijenaz-1; mikroglia; inflamasyon
• ISSN: 1304-530X; 2148-6247
• DOI: 10.4274/tjps.58966

The lipid peroxidation-derived aldehyde 4-hydroxynonenal (HNE) has been implicated in a number of oxidative stress-induced inflammatory pathologies such as neurodegenerative diseases and aging. In this regard, we investigated the effects of HNE on neuroinflammatory responses by measuring cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) induction with cytokine production. In addition, we measured nuclear factor erythroid 2-related factor 2 (Nrf-2)/Kelch-like ECH-associated protein 1 (Keap1) signaling proteins, and antioxidant enzymes heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1), and compared the results with quercetin and monochloropivaloylquercetin (MPQ) pretreated microglial cells. Cytotoxicity was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and production of cytokines was determined by cytokine array. Furthermore, intracellular Nfr2/Keap1 signaling proteins, HO-1, NQO1, and COX-2 expression were analyzed by western blot in 2.5 μM HNE treated BV-2 cells. Inducible nitric oxide synthase (iNOS) and COX-2 mRNA levels were measured with reverse transcription-quantitative polymerase chain reaction. HNE induced both COX-2 mRNA and protein levels, iNOS mRNA expression, and cytokine production. In addition, HNE markedly increased Keap1 levels and decreased cytoplasmic Nrf-2 expression with antioxidant enzyme HO-1 levels. Quercetin and monochloropivaloylquercetin treatment alleviated neuroinflammatory responses in microglial cells, by decreasing COX-2 mRNA expression. Monochloropivaloylquercetin decreased cytoplasmic Keap1 levels and increased nuclear translocation of Nrf-2 resulted in induction of HO-1 and NQO1 expression. These results suggest that HNE could be a link between oxidative stress and inflammation in BV-2 microglia cells. In particular, monochloropivaloylquercetin alleviated inflammation, probably by decreasing the expression of proinflammatory genes and strengthening the antioxidant defense system.