• The Journal of Korean Medicine
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• v.22 no.4
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• pp.45-57
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• 2001

Objectives : The water extract of Gwibitang (GBT) has been traditionally used for treatment of psychologic disease and brain damage in Oriental Medicine, This study was designed to investigate the effect of GBT on the glutamate-induced toxicity of rat C6 glial cells. Methods : The cultured cells were pretreated with GBT and exposed to glutamate, The cell damage was assessed by using MTT assay and Hoechst, IC-l staining, Results : GBT had protective effects in glutamate-induced cytotoxicity, which was revealed as apoptosis characterized by chromatic condensation and the loss of mitochondrial membrane potential in C6 glial cells. However, GBT and glutamate had no effect in the activation of caspase family cysteine proteases including caspase-3, -8 and -9 proteasesin C6 glial ce]]s, GBT significantly recovered the depletion of GSH and inhibited the generation of $H_2O_2$ by glutamate in C6 glial cells. In addition, both GBT and antioxidants such as GSH and NAC protected the glutamate-induced cytotoxicity in C6 glial cells, indicating that GBT possibly has antioxidative effect. Moreover, GBT also inhibited the glutamate-induced degradation of $IkB{\alpha}$ in C6 glial cells, This result suggest that GBT has some inhibitory effects on the transcriptional activation of $NF-_{k}B$. Conclusions : GBT has protective effects in glutamate-induced cytotoxicity via an antioxidative mechanism.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.309-318
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• 2024

Compared to other organs, the brain has limited antioxidant defenses. In particular, the hippocampus is the central region for learning and memory and is highly susceptible to oxidative stress. Glial cells are the most abundant cells in the brain, and sustained glial cell activation is critical to the neuroinflammation that aggravates neuropathology and neurotoxicity. Therefore, regulating glial cell activation is a promising neurotherapeutic treatment. Quinic acid (QA) and its derivatives possess anti-oxidant and anti-inflammatory properties. Although previous studies have evidenced QA's benefit on the brain, in vivo and in vitro analyses of its anti-oxidant and anti-inflammatory properties in glial cells have yet to be established. This study investigated QA's rescue effect in lipopolysaccharide (LPS)-induced behavior impairment. Orally administering QA restored social impairment and LPS-induced spatial and fear memory. In addition, QA inhibited proinflammatory mediator, oxidative stress marker, and mitogen-activated protein kinase (MAPK) activation in the LPS-injected hippocampus. QA inhibited nitrite release and extracellular signal-regulated kinase (ERK) phosphorylation in LPS-stimulated astrocytes. Collectively, QA restored impaired neuroinflammation-induced behavior by regulating proinflammatory mediator and ERK activation in astrocytes, demonstrating its potential as a therapeutic agent for neuroinflammation-induced brain disease treatments.

• IMMUNE NETWORK
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• v.12 no.2
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• pp.41-47
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• 2012

Contemporary studies illustrate that peripheral injuries activate glial components of the peripheral and central cellular circuitry. The subsequent release of glial stressors or activating signals contributes to neuropathic pain and neuroinflammation. Recent studies document the importance of glia in the development and persistence of neuropathic pain and neuroinflammation as a connecting link, thereby focusing attention on the glial pathology as the general underlying factor in essentially all age-related neurodegenerative diseases. There is wide agreement that excessive glial activation is a key process in nervous system disorders involving the release of strong pro-inflammatory cytokines, which can trigger worsening of multiple disease states. This review will briefly discuss the recent findings that have shed light on the molecular and cellular mechanisms of glia as a connecting link between neuropathic pain and neuroinflammation.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.5
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• pp.237-243
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• 2004

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCl). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.6
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• pp.1423-1430
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• 2008

The water extract of Sopung-tang(SPT) has been traditionally used for treatment of psycologic disease and brain damage in oriental medicine. However, little is known about the mechanism by which the water extract of SPT rescues cells from these disease. Therefore, this study was designed to investigate the effect of SPT on the glutamate-induced toxicity of rat C6 glial cells. SPT have protective effects in glutamate-induced toxicity, which was revealed as apoptosis characterized by chromatic condensation and fragmentation and the loss of mitochondrial membrane potential in C6 glial cells. Also, SPT have inhibited the active form of caspase-3 and PARP and significantly protected the apoptotic phenomena by glutamate toxicity in C6 glial cells. However, SPT significantly recovered the depletion of GSH and inhibited the generation of ROS by glutamate in C6 glial cells. In addition, both SPT and antioxidants such as GSH and NAC protected the glutamate-induced cytotoxicity in C6 glial cells, indicating that SPT possibly have antioxidative effect. Specially, SPT were showed transcriptional factor significantly increased the activation of NF-${\kappa}B$ using the analysis of NF-${\kappa}B$ luciferase reporter system in C6 glial cells. These NF-${\kappa}B$ activation protected cells from glutamate-induced toxicity to generate the heme oxygenase-1(HO-1). Taken together, we suggest that SPT have protective effects in glutamate-induced toxicity via a antioxidative mechanism.

• IMMUNE NETWORK
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• v.13 no.4
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• pp.141-147
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• 2013

Hypoxia has been shown to promote inflammation, including the release of proinflammatory cytokines, but it is poorly investigated how hypoxia directly affects inflammasome signaling pathways. To explore whether hypoxic stress modulates inflammasome activity, we examined the effect of cobalt chloride ($CoCl_2$)-induced hypoxia on caspase-1 activation in primary mixed glial cultures of the neonatal mouse brain. Unexpectedly, hypoxia induced by oxygen-glucose deprivation or $CoCl_2$ treatment failed to activate caspase-1 in microglial BV-2 cells and primary mixed glial cultures. Of particular interest, $CoCl_2$-induced hypoxic condition considerably inhibited NLRP3-dependent caspase-1 activation in mixed glial cells, but not in bone marrow-derived macrophages. $CoCl_2$-mediated inhibition of NLRP3 inflammasome activity was also observed in the isolated brain microglial cells, but $CoCl_2$ did not affect poly dA:dT-triggered AIM2 inflammasome activity in mixed glial cells. Our results collectively demonstrate that $CoCl_2$-induced hypoxia may negatively regulate NLRP3 inflammasome signaling in brain glial cells, but its physiological significance remains to be determined.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2003.11a
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• pp.84-84
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• 2003

Lead has long been considered as a toxic environmental pollutant, which severely damages central nervous system. Lead can cause hypo- and de-myelination, and glial cells are closely related with myelination or demyelination. Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in the remodelling of the extracellular matrix in a variety of physiological and pathological processes. MMPs also seem to be important in the pathogenesis of inflammatory demyelinating diseases of the central and peripheral nervous system. In this study, we investigated whether lead affects MMP-9 expression in rat primary glial cells. Treatment of 0.1-5 ${\mu}$M lead dose- and time-dependently increased MMP-9 expression in rat primary glial cells. The activity of MMPs was determined using zymography. Lead activated Erk(1/2) but neither of the other endogenous MAP kinases, p38 or JNK. Inhibition of Erk(1/2) activation by PD98059, a MEK inihibitor, prevented lead-induced expression of MMP-9. The results of the present study suggest that lead intoxication may adversely affect brain function at least in part by inducing MMP-9 expression through Erk(1/2) activation in primary glial cells.

• The Korean Journal of Pain
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• v.22 no.1
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• pp.1-15
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• 2009

Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.6
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• pp.1004-1011
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• 2010

This study was designed to evaluate the protective effects of Dodamtanggami-bang (DDTG) on tunicamycin induced cell death by ER stress in C6 glial cells. Cell viability was measured by MTT assay and LDH release. Apoptosis was determined by caspase activity and flow cytometry in C6 glial cells. Expression of ER stress mediators including, GRP78 and CHOP proteins were measured by Western blot analysis. Tunicamycin induced the apoptosis of C6 glial cells, which was characterized as nucleic acid and caspase-3 activation, PARP cleavage, and sub-G0/G1 fraction of cell cycle increase. However, pretreatment with DDTG protected C6 glial cells from tunicamycin. Treatment with tunicamycin resulted in the increased the expression of GRP78 and CHOP protein and produced ROS generation. However, pretreatment with DDTG inhibited the ER stress pathway, including increase of the expression of GRP78, CHOP proteins in C6 glial cells treated with tunicamycin. Taken together, these data suggest that DDTG is able to protect C6 glial cells from tunicamycin with marked inhibition of ER stress.

• The Journal of Internal Korean Medicine
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• v.31 no.3
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• pp.586-599
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• 2010

Objective : The water extract of Yukgunja-tang(YGJT) has been traditionally used in treatment of qi deficiency and phlegm in Oriental medicine. However, little is known about the mechanism by which YGJT protects neuronal cells from injury damages. Therefore, this study was designed to evaluate the protective effects of YGJT on C6 glial cells by glutamate-induced cell death. Methods : The present study describes glutamate, which is known as an excitatory neurotransmitter, related with oxidative damages, and YGJT, which shows protective effects against glutamate-induced C6 glial cell death. One of the main mediators of glutamate-induced cytotoxicity was known on the generation of reactive oxygen species(ROS) via activation of NADPH oxidase (NOX). The protective effects of antioxidant(NAC) and NOX inhibitor(apocynin) on the glutamate-induced C6 glial cells were determined by a MTT reduction assay. Result : YGJT inhibited glutamate-induced ROS generation via inhibition of NOX expression on glutamate-stimulated C6 glial cells. Furthermore, YGJT attenuated glutamate-induced caspase activation. These results suggest that YGJT could be a new potential candidate against glutamate-induced oxidative stress and cell death. Conclusion : These findings indicate that in C6 glial cells, ROS plays an important role of glutamate-induced cell death and that YGJT may prevent cell death from glutamate-induced cell death by inhibiting the ROS generation.