Licochalcone A Inhibits Prostaglandin E2 by Targeting the MAPK Pathway in LPS Activated Primary Microglia.

Neuroinflammation and oxidative stress are conditions leading to neurological and neuropsychiatric disorders. Natural compounds exerting anti-inflammatory and anti-oxidative effects, such as Licochalcone A, a bioactive flavonoid present in a traditional Chinese herb (licorice), might be beneficial for the treatment of those disorders. Therefore, this study aimed to investigate the anti-inflammatory and anti-oxidative effects of Licochalcone A in LPS-activated primary rat microglia. Licochalcone A dose-dependently prevented LPS-induced PGE2 release by inhibiting the arachidonic acid (AA)/cylcooxygenase (COX) pathway decreasing phospholipase A2, COX-1, and COX-2 protein levels. Furthermore, LPS-induced levels of the cytokines IL-6 and TNFα were reduced by Licochalcone A, which also inhibited the phosphorylation and, thus, activation of the mitogen-activated protein kinases (MAPK) p38 MAPK and Erk 1/2. With the reduction of 8-iso-PGF2α, a sensitive marker for oxidative stress, anti-oxidative effects of Licochalcone A were demonstrated. Our data demonstrate that Licochalcone A can affect microglial activation by interfering in important inflammatory pathways. These in vitro findings further demonstrate the potential value of Licochalcone A as a therapeutic option for the prevention of microglial dysfunction related to neuroinflammatory diseases. Future research should continue to investigate the effects of Licochalcone A in different disease models with a focus on its anti-oxidative and anti-neuroinflammatory properties.

Rice bran derivatives alleviate microglia activation: possible involvement of MAPK pathway.

BACKGROUND: Hyperactivation of microglia is considered to be a key hallmark of brain inflammation and plays a critical role in regulating neuroinflammatory events. Neuroinflammatory responses in microglia represent one of the major risk factors for various neurodegenerative diseases. One of the strategies to protect the brain and slow down the progression of these neurodegenerative diseases is by consuming diet enriched in anti-oxidants and polyphenols. Therefore, the present study aimed to evaluate the anti-inflammatory effects of rice bran extract (RBE), one of the rich sources of vitamin E forms (tocopherols and tocotrienols) and gamma-oryzanols, in primary rat microglia. METHODS: The vitamin E profile of the RBE was quantified by high-performance liquid chromatography (HPLC). Microglia were stimulated with lipopolysaccharide (LPS) in the presence or absence of RBE. Release of prostaglandins (prostaglandin (PG) E2, 8-iso-prostaglandin F2α (8-iso-PGF2α)) were determined with enzyme immunoassay (EIA). Protein levels and genes related to PGE2 synthesis (Cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1)) and various pro- and anti-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-10), were assessed by western blot, ELISA, and quantitative real-time PCR. Furthermore, to elucidate the molecular targets of RBE, the phosphorylated state of various mitogen-activated protein kinase (MAPK) signaling molecules (p38 MAPK, ERK 1/2, and JNK) and activation of NF-kB pathway was studied. RESULTS: RBE significantly inhibited the release of PGE2 and free radical formation (8-iso-PGF2α) in LPS-activated primary microglia. Inhibition of PGE2 by RBE was dependent on reduced COX-2 and mPGES-1 immunoreactivity in microglia. Interestingly, treatment of activated microglia with RBE further enhanced the gene expression of the microglial M2 marker IL-10 and reduced the expression of pro-inflammatory M1 markers (TNF-α, IL-1ß). Further mechanistic studies showed that RBE inhibits microglial activation by interfering with important steps of MAPK signaling pathway. Additionally, microglia activation with LPS leads to IkB-α degradation which was not affected by the pre-treatment of RBE. CONCLUSIONS: Taken together, our data demonstrate that RBE is able to affect microglial activation by interfering in important inflammatory pathway. These in vitro findings further demonstrate the potential value of RBE as a nutraceutical for the prevention of microglial dysfunction related to neuroinflammatory diseases, including Alzheimer's disease.