• Proceedings of the PSK Conference
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• 2003.10b
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• pp.79.2-79.2
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• 2003

Minocycline is known to protect neurons from microglia-mediated cell death in many experimental models of brain diseases including ischemic stroke, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, and Parkinson's disease. Activation of caspase-2, 3, 8, and 9 was evident within 2-8 hr following oxidative insult with 0.5 mM hydrogen peroxide in PC12 cells. Minocycline significantly attenuated activation of these caspases up to 18 hr, resulting a significant increase in cell viability as assessed by MTT assay. (omitted)

• The Korea Journal of Herbology
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• v.29 no.2
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• pp.33-38
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• 2014

Objectives : Inflammation is mediated by cellular components, such as leukocytes and microglia, and molecular components, including cytokines, extracellular proteases, and reactive oxygen species. Cnidium Rhizoma effects the anti-inflammatory, antioxidant, suppression of the microglia activation and protection of the nerve cell injury. For this reason, we investigated the anti-inflammatory effects of water extracts of Cnidium Rhizoma on intracerebral hemorrhage (ICH). Method : ICH was induced by the stereotaxic intracerebral injection of bacterial collagenase type IV (0.23 $U/{\mu}{\ell}$, 0.1 ${\mu}{\ell}/min$) in Sprague-Dawley rats. We orally administrated once 3 hours after ICH, then 2 times at 24-hour intervals the water extracts of Cnidium Rhizoma (500 mg/kg), myeloperoxidase (MPO) was observed by using immunofluorescense and expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and microglia were observed by using immunohistochemistry. Results : Infiltration of MPO expressing neutrophil, expression of iNOS and TNF-${\alpha}$ and activated microglia were significantly reduced in peri-hematoma of the rats fed with water extracts of Cnidium Rhizoma. Conclusion : These results demonstrated that water extracts of Cnidium Rhizoma suppressed an inflammatory reaction through inhibition of MPO, iNOS and TNF-${\alpha}$ positive cell and activated microglia number in peri-hematoma of ICH-induced rats.

• BMB Reports
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• v.54 no.12
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• pp.620-625
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• 2021

Microglia are known to be activated in the hypothalamic paraventricular nucleus (PVN) of rats with cardiovascular diseases. However, the exact role of microglial activation in the plasticity of presympathetic PVN neurons associated with the modulation of sympathetic outflow remains poorly investigated. In this study, we analyzed the direct link between microglial activation and spontaneous firing rate along with the underlying synaptic mechanisms in PVN neurons projecting to the rostral ventrolateral medulla (RVLM). Systemic injection of LPS induced microglial activation in the PVN, increased the frequency of spontaneous firing activity of PVN-RVLM neurons, reduced GABAergic inputs into these neurons, and increased plasma NE levels and heart rate. Systemic minocycline injection blocked all the observed LPS-induced effects. Our results indicate that LPS increases the firing rate and decreases GABAergic transmission in PVN-RVLM neurons associated with sympathetic outflow and the alteration is largely attributed to the activation of microglia. Our findings provide some insights into the role of microglial activation in regulating the activity of PVN-RVLM neurons associated with modulation of sympathetic outflow in cardiovascular diseases.

• Journal of Life Science
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• v.33 no.6
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• pp.455-462
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• 2023

During pregnancy, maternal immune activation (MIA) from infection increases the risk of neurodevelopmental diseases, including schizophrenia and autism spectrum disorders. MIA induced by polyinosinic-polycytidylic acid (poly (I:C)) and lipopolysaccharide (LPS) in animal experiments has led to offspring with abnormal behaviors and brain development. In addition, it has recently been reported that microglia, which reside in the brain and function as immune cells, play an important role in behavioral abnormalities and brain development in MIA-induced offspring. However, the underlying mechanism remains unclear. In this study, we investigated whether microglia-specific inhibition of GPR56, a member of the G protein-coupled receptor (GPCR) family, causes behavioral abnormalities in brain development. First, MIA induction did not affect the microglia population, but when examining the expression of microglial GRP56 in MIA-induced fetuses, GPR56 expression was inhibited between embryonic days 14.5 (E14.5) and E18.5 regardless of sex. Furthermore, microglial GPR56-suppressed mice showed abnormal behaviors in the MIA-induced offspring, including sociability deficits, repetitive behavioral patterns, and increased anxiety levels. Although abnormal cortical development such as that in the MIA-induced offspring were not observed in the microglial GPR56-suppressed mice, their brain activity was observed through c-fos staining. These results suggest that microglia-specific GPR56 deficiency may cause abnormal behaviors and could be used as a biomarker for the diagnosis and/or as a therapeutic target of behavioral deficits in MIA offspring.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.43-48
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• 2012

Glutamate excitotoxicity is emerging as a contributor to degeneration of spinal cord motoneurons in amyotrophic lateral sclerosis (ALS). Recently, we have reported that ghrelin protects motoneurons against chronic glutamate excitotoxicity through the activation of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-$3{\beta}$ pathways. Previous studies suggest that activated microglia actively participate in the pathogenesis of ALS motoneuron degeneration. However, it is still unknown whether ghrelin exerts its protective effect on motoneurons via inhibition of microglial activation. In this study, we investigate organotypic spinal cord cultures (OSCCs) exposed to threohydroxyaspartate (THA), as a model of excitotoxic motoneuron degeneration, to determine if ghrelin prevents microglial activation. Exposure of OSCCs to THA for 3 weeks produced typical motoneuron death, and treatment of ghrelin significantly attenuated THA-induced motoneuron loss, as previously reported. Ghrelin prevented THA-induced microglial activation in the spinal cord and the expression of pro-inflammatory cytokines tumor necrosis factor-${\alpha}$ and interleukin-$1{\beta}$. Our data indicate that ghrelin may act as a survival factor for motoneurons by functioning as a microglia-deactivating factor and suggest that ghrelin may have therapeutic potential for the treatment of ALS and other neurodegenerative disorders where inflammatory responses play a critical role.

• Archives of Pharmacal Research
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• v.26 no.12
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• pp.1067-1073
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• 2003

Ursodeoxycholic acid (UDCA) is a non-toxic, hydrophilic bile acid in widespread clinical use mainly for acute and chronic liver disease. Recently, treatment with UDCA in hepatic graft-versus-host disease has been given in immunosuppressive therapy for improvement of the biochemical markers of cholestasis. Moreover, it has been reported that UDCA possesses immunomodulatory effects by the suppression of cytokine production. In the present study, we hypothesized that UDCA may inhibit the production of the pro-inflammatory cytokine, IL-1$\beta$, and nitric oxide (NO) in microglia. In the study, we found that 100 $\mu$ g/mL UDCA effectively inhibited these two pro-inflammatory factors at 24 hand 48 h, compared to the $A\beta$42-pretreated groups. These results were compared with the LPS+UDCA group to confirm the UDCA effect. As microglia can be activated by several stimulants, such as $A\beta$42, in Alzheimers brain and can release those inflammatory factors, the ability to inhibit or at least decrease the production of IL-1$\beta$ and NO in Alzheimers disease (AD) is essential. Using RT-PCR, ELISA and the Griess Reagent System, we therefore found that UDCA in $A\beta$42 pre-treated cultures played a significant role in suppressing the expression or the production of IL-1$\beta$ and NO. Similarly, lipopolysaccharide (LPS) did not activate microglia in the presence of UDCA. Moreover, we found that UDCA exhibits a prolonged effect on microglial cells (up to 48 h), which suggests that UDCA may play an important role in chronic cell damage due to this long effect. These results further imply that UDCA could be an important cue in suppressing the microglial activation stimulated by massive AD peptides in the AD progressing brain.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.5
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• pp.738-744
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• 2012

Gastrodia elata Blume is used for a variety of purposes including treatment of inflammation in the Korean medicine. The present study investigated whether the G. elata extracts have the anti-inflammatory effect on lipopolysaccharide(LPS)-stimulated BV-2 microglia cells. G. elata extracts showed an anti-inflammatory effects in the morphological and nitric oxide(NO) analysis, especially in hexane extract. So we investigated the hexane extract from G. elata in the following experiments. Hexane extract significantly inhibited the secretion of NO with protein level of inducible nitric oxide synthase in LPS-stimulated BV2 microglia cells. Hexane extract also inhibited LPS-stimulated inflammatory responses involving the degradation of cytosolic inhibitory(I)-${\kappa}B{\alpha}$ and the translocation of nuclear factor(NF)-${\kappa}Bp65$ to nucleus in LPS-stimulated BV-2 microglia cells by morphological analysis. Western blot analyse confirmed that I-${\kappa}B{\alpha}$ and NF-${\kappa}Bp65$ showed a similar pattern as morphological analysis. Our results suggest that G. elata extracts, especially hexane extract, may act as a therapeutic agent for inflammatory disease in the central nervous system through a selective regulation of NO production and NF-${\kappa}B$ activation.

• Journal of Korean Neurosurgical Society
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• v.49 no.2
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• pp.83-91
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• 2011

Objective : Minocycline, a second-generation tetracycline-class antibiotic, has been well established to exert a neuroprotective effect in animal models and neurodegenerative disease through the inhibition of microglia. Here, we investigated the effects of minocycline on motor recovery and neuropathic pain in a rat model of spinal cord injury. Methods : To simulate spinal cord injury, the rats' spinal cords were hemisected at the 10th thoracic level (T10). Minocycline was injected intraperitoneally, and was administered 30 minutes prior surgery and every second postoperative day until sacrifice 28 days after surgery. Motor recovery was assessed via the Basso-Beattie-Bresnahan test Mechanical hyperalgesia was measured throughout the 28-day post -operative course via the von Frey test Microglial and astrocyte activation was assessed by immunohistochemical staining for ionized calcium binding adaptor molecule 1 (lba1) and glial fibrillary acidic protein (GFAP) at two sites: at the level of hemisection and at the 5th lumbar level (L5). Results : In rats, spinal cord hemisection reduced locomotor function and induced a mechanical hyperalgesia of the ipsilateral hind limb. The expression of lba1 and GFAP was also increased in the dorsal and ventral horns of the spinal cord at the site of hemisection and at the L5 level. Intraperitoneal injection of minocycline facilitated overall motor recovery and attenuated mechanical hyperalgesia. The expression of lba1 and GFAP in the spinal cord was also reduced in rats treated with minocycline. Conclusion : By inhibiting microglia and astrocyte activation, minocycline may facilitate motor recovery and attenuate mechanical hyperalgesia in individuals with spinal cord injuries.

• The Korea Journal of Herbology
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• v.23 no.3
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• pp.73-83
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• 2008

Objectives : The root of Zingiber officinale ROSC. (Zingiberis Rhizoma Recens; Ginger) has been widely used as one of folk remedies and food materials in many traditional preparations. Ginger is known as an effective appetite enhancer and anti-inflammatory agent. This study was performed to investigate the effect of ginger chloroform fraction (GCF) in microglia which play a central role on brain inflammation in neurodegenerative diseases. Methods : Dried ginger was extracted with 80% methanol, and then fractionated with chloroform. BV2 mouse microglial cells were cultured with different concentrations of GCF and then stimulated with LPS (1 ${\mu}g/m{\ell}$) at indicated times. The cell toxicity of GCF was determined by MTT assay. The concentrations of NO, PGE2 and cytokines were measured by Griess assay and enzyme-linked immunosorbant assay. The mRNA and protein expressions of iNOS, COX-2 and cytokines were determined by RT-PCR and Western blotting. The phosphorylation of three MAPKs (p38 MAPK, ERK1/2 and JNK) and $NF-{\kappa}B$ activation were determined by Western blotting. Results : GCF significantly inhibited LPS-induced production of inflammatory mediators, NO, $PGE_2$ and proinflammatory cytokines ($TNF-{\alpha}$ and $IL-1{\beta}$) in a dose-dependent manner. GCF attenuated LPS-induced expression of mRNA and protein of inflammatory enzymes, iNOS, COX-2 and proinflammatory cytokines through suppressing the phosphorylation of ERK1/2 and p38 MAPK and the activation of p65 $NF-{\kappa}B$ in BV2 cells. Conclusions : This study suggests that GCF may have an anti-inflammatory property through suppressing the inflammatory mediator production released by activated microglia after the brain injury.

• The Journal of Korean Medicine
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• v.43 no.4
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• pp.20-32
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• 2022

Objectives: Kyungok-go (KOG) is a traditional multi-herbal medicine commonly used for enforcing weakened immunity for long time. Recently, there are several reports that KOG has anti-inflammatory and immuno-stimulatory activities in many experimental models. However, the protective effects of KOG on neuronal inflammation are still undiscovered. Thus, we investigated the neuro-protective activity of KOG on lipopolysaccharide (LPS)-stimulated mouse microglia cells. To find out KOG's anti-neuroinflammatory effects on microglial cells, we examined the production of nitrite using griess assay, and mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α using real time RT-PCR. In addition, to examine the regulating mechanisms of KOG, we investigated the protein expression of mitogen-activated protein kinases (MAPKs) and Iκ-Bα by western blot. KOG inhibited the elevation of nitrite, iNOS and COX-2 on LPS-stimulated BV2 cells. Also, KOG significantly inhibited the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α on LPS-stimulated BV2 microglial cells. Moreover, KOG inhibited the activation of c-Jun N-terminal kinase (JNK), P38 and degradation of Iκ-Bα but not the activation of extracellular signal regulated kinase (ERK) on LPS-stimulated BV2 microglial cells. These results showed KOG has the anti-inflammatory effects through the inhibition on nitrite, iNOS, COX-2, IL-1β, IL-6, and TNF-α via the deactivation of JNK, p38 and nuclear factor (NF)-κB on LPS-stimulated BV2 microglial cells. Thereby, KOG could offer the new and promising treatment for neurodegenerative disease related to neuroinflammation.