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ERIC Number: ED526766
Record Type: Non-Journal
Publication Date: 2009
Pages: 136
Abstractor: As Provided
Reference Count: 0
ISBN: ISBN-978-1-1095-7499-9
Beneficial Effect of the Flavonoid Luteolin on Neuroinflammation
Jang, Saebyeol
ProQuest LLC, Ph.D. Dissertation, University of Illinois at Urbana-Champaign
Excessive production of pro-inflammatory mediators by activated brain microglia plays an important role in abnormal neuronal function and cognitive deficits. Studies have shown that the intake of flavonoids is inversely related to cognitive decline and dementia in people 65 years of age or older. Luteolin, a flavonoid found in high concentrations in celery, green pepper, and perilla leaf and seeds, has been shown to reduce pro-inflammatory molecules produced by lipopolysaccharide (LPS)-stimulated macrophages, fibroblasts, and intestinal epithelial cells. However, the anti-inflammatory effects of luteolin on neuroinflammation have not been studied. Therefore, we investigated whether luteolin may attenuate neuroinflammation mediated by activated microglia and subsequently modulate age-associated cognitive decline. Initially, we observed the anti-inflammatory and neuroprotective effects of luteolin "in vitro". Luteolin inhibited LPS-stimulated production of tumor necrosis factor (TNF)-[alpha] and interleukin (IL)-1[beta] at both the gene and protein levels in BV-2 microglial cells. Luteolin also suppressed LPS-induced nitric oxide (NO) and prostaglandin (PG) E [subscript 2] by regulating mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxigenase (COX)-2, respectively. Treatment of Neuro.2a neuronal cells with conditioned media from LPS-stimulated microglia resulted in neuronal cell death. More importantly, treating microglia with luteolin prior to LPS reduced neuronal cell death in a dose-dependent manner. Additionally, we sought to determine whether luteolin also regulates IL-6 production and the mechanism by which luteolin exerts this anti-inflammatory effect. Pretreatment of primary murine microglia and BV-2 cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. Moreover, we found that this anti-inflammatory effect of luteolin works through c-Jun-N-terminal kinase (JNK) and transcription factor, activator protein-1 (AP-1). Luteolin also had similar anti-inflammatory effects "in vivo". In adult mice, drinking water supplemented with luteolin for three weeks reduced LPS-induced IL-6 in plasma and hippocampus 4 h after peripheral injection of LPS. Finally, given these potent anti-inflammatory properties of luteolin, as well as the inverse relationship between flavonoid intake and cognitive decline in older persons and aged animals reported by others, we explored whether dietary supplementation of luteolin can ameliorate age-related deficits in spatial working memory and reduce inflammatory molecules in aged brain. Adult and aged mice were provided control or luteolin supplemented diet for four weeks. Dietary supplementation of luteolin attenuated the age-related spatial working memory deficits along with alleviating hippocampal IL-1[beta] and major histocompatibility complex (MHC) class II mRNA expression in aged mice. Collectively, these studies showed that luteolin might be a promising agent for preventing neuroinflammation and neuronal cell death mediated by activated microglia and consequently, attenuating age-associated cognitive decline. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page:]
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Publication Type: Dissertations/Theses - Doctoral Dissertations
Education Level: N/A
Audience: N/A
Language: English
Sponsor: N/A
Authoring Institution: N/A