BackgroundMicroglial activation plays an important role in neurodegenerative diseases by producing several proinflammatory enzymes and proinflammatory cytokines. The phenolic glucoside gastrodin, a main constituent of a Chinese herbal medicine, has been known to display anti-inflammatory properties. The current study investigates the potential mechanisms whereby gastrodin affects the expression of potentially pro-inflammatory proteins by cultured murine microglial BV-2 cells stimulated with lipopolysaccharide (LPS).Methodology/Principal FindingsBV-2 cells were pretreated with gastrodin (30, 40, and 60 µM) for 1 h and then stimulated with LPS (1 µg/ml) for another 4 h. The effects on proinflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and proinflammatory cytokines, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), are analysed by double-immunofluorescence labeling and RT-PCR assay. To reveal the mechanisms of action of gastrodin we investigated the involvement of mitogen-activated protein kinases (MAPKs) cascades and their downstream transcription factors, nuclear factor-κB (NF-κB) and cyclic AMP-responsive element (CRE)-binding protein (CREB). Gastrodin significantly reduced the LPS-induced protein and mRNA expression levels of iNOS, COX-2, TNF-α, IL-1β and NF-κB. LPS (1 µg/ml, 30 min)-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) and this was inhibited by pretreatment of BV-2 cells with different concentrations of gastrodin (30, 40, and 60 µM). In addition, gastrodin blocked LPS-induced phosphorylation of inhibitor κB-α (IκB-α) (and hence the activation of NF-κB) and of CREB, respectively.Conclusion and ImplicationsThis study indicates that gastrodin significantly attenuate levels of neurotoxic proinflammatory mediators and proinflammatory cytokines by inhibition of the NF-κB signaling pathway and phosphorylation of MAPKs in LPS-stimulated microglial cells. Arising from the above, we suggest that gastrodin has a potential as an anti-inflammatory drug candidate in neurodegenerative diseases.

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BackgroundResveratrol have been known to possess many pharmacological properties including antioxidant, cardioprotective and anticancer effects. Although current studies indicate that resveratrol produces neuroprotection against neurological disorders, the precise mechanisms for its beneficial effects are still not fully understood. We investigate the effect of anti-inflammatory and mechamisms of resveratrol by using lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells.Methodology/Principal FindingsBV-2 cells were treated with resveratrol (25, 50, and 100 µM) and/or LPS (1 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of PTEN (phosphatase and tensin homolog deleted on chromosome 10), Akt, mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) cascades, inhibitor κB-α (IκB-α) and cyclic AMP-responsive element-binding protein (CREB) were measured by western blot. Resveratrol significantly attenuated the LPS-induced expression of NO, PGE2, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB) in BV-2 cells. Resveratrol increased PTEN, Akt and mTOR phosphorylation in a dose-dependent manner or a time-dependent manner. Rapamycin (10 nM), a specific mTOR inhibitor, blocked the effects of resveratrol on LPS-induced microglial activation. In addition, mTOR inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of IκB-α, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK).Conclusion and ImplicationsThis study indicates that resveratrol inhibited LPS-induced proinflammatory enzymes and proinflammatory cytokines via down-regulation phosphorylation of NF-κB, CREB and MAPKs family in a mTOR-dependent manner. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of resveratrol.

Background The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms. Methods A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)–EGFP infusion. Results The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors. Conclusion These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric mood disorder that lacks objective laboratory-based tests to support its diagnosis. A class of microRNAs (miRNAs) has been found to be centrally involved in regulating many molecular processes fundamental to central nervous system function. Among these miRNAs, miRNA-134 (miR-134) has been reported to be related to neurogenesis and synaptic plasticity. In this study, the hypothesis that plasma miR-134 can be used to diagnose MDD was tested. Perturbation of peripheral and central miR-134 in a depressive-like rat model was also examined. By reverse-transcription quantitative PCR, miR-134 was comparatively measured in a small set of plasma samples from MDD and healthy control (HC) subjects. To determine its diagnostic efficacy, plasma miR-134 levels were assessed in 100 MDD, 50 bipolar disorder (BD), 50 schizophrenic (SCZ), and 100 HC subjects. A chronic unpredictable mild stress (CUMS) rat model was also developed to evaluate miR-134 expression in plasma, hippocampus (HIP), prefrontal cortex (PFC), and olfactory bulb. We found that plasma miR-134 was significantly downregulated in MDD subjects. Diagnostically, plasma miR-134 levels could effectively distinguish MDD from HC with 79% sensitivity and 84% specificity, while distinguishing MDD from HC, BD, and SCZ subjects with 79% sensitivity and 76.5% specificity. Congruent with these clinical findings, CUMS significantly reduced miR-134 levels in the rat plasma, HIP, and PFC. Although limited by the relatively small sample size, these results demonstrated that plasma miR-134 displays potential ability as a biomarker for MDD.

Microglia mediated neuroinflammation is known to cause various neurodegenerative and neurological ailments. Tannic acid is a natural polyphenol which has been reported to possess antioxidant, anti‐inflammatory, anticarcinogenic, antimutagenic, antitumor, and antimicrobial activities. As there are no reports till date on the anti‐neuroinflammatory effects of tannic acid, this study was conducted to analyze the possible mechanism and pathway involved in the prevention of neuroinflammation by tannic acid in BV2 microglial cells. BV2 microglial cells were pretreated with tannic acid (10, 25, and 50 μM/mL) and induced with lipopolysaccharide (LPS; 1 μM/mL) to assess the production of reactive oxygen species (ROS), nitric oxide (NO), prostaglandin E2 (PGE2), pro‐inflammatory cytokines (IL‐6, IL‐1β, and TNF‐α), and nuclear factor‐kappa B (NF‐κB) protein expressions through western blotting. The results showed that LPS significantly activated the BV2 cells via toll‐like receptor 4 to induce elevated productions of ROS, NO, PGE2, IL‐6, and IL‐1β. However, tannic acid was able to reverse all the neuroinflammatory effects of LPS‐induced BV2 cells in a dose‐dependent manner. Collectively, the anti‐inflammatory effects of tannic acid on LPS‐induced BV2 microglial cells are attributed to the inhibition of ROS formation and the suppression of NF‐κB pathway activation. Tannic acid could be a potential therapeutic agent for the treatment of neurological related disorders.

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