• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.519-527
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• 2017

Excessive activation of microglia causes the continuous production of neurotoxic mediators, which further causes neuron degeneration. Therefore, inhibition of microglial activation is a possible target for the treatment of neurodegenerative disorders. Balanophonin, a natural neolignoid from Firmiana simplex, has been reported to have anti-inflammatory and anti-cancer effects. In this study, we aimed to evaluate the anti-neuroinflammatory effects and mechanism of balanophonin in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of balanophonin. The results indicated that balanophonin reduced not only the LPS-mediated TLR4 activation but also the production of inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), $Interleukin-1{\beta}$ ($IL-1{\beta}$), and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), in BV2 cells. Balanophonin also inhibited LPS-induced inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) protein expression and mitogen activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 MAPK. Interestingly, it also inhibited neuronal cell death resulting from LPS-activated microglia by regulating cleaved caspase-3 and poly ADP ribose polymerase (PARP) cleavage in N2a cells. In conclusion, our data indicated that balanophonin may delay the progression of neuronal cell death by inhibiting microglial activation.

• The Korea Journal of Herbology
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• v.21 no.4
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• pp.93-101
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• 2006

Objectives : Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease(AD), Parkinson's disease(PD) and Huntington's disease(HD) in the inflammatory process. Uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines ($TNF-{\alpha}$, $IL-1{\beta}$ and IL-6), NO, PEG2 and superoxide. In this study, the immunomodulatory effects of the herbal extract Panax notoginseng on cultured BV2 microglial cells and primary microglia were investigated to address potential therapeutic or toxic effects. Notoginseng radix extracts extracted from the root of the plant using Methanol. Methods : Cells were stimulated with LPS and treated with notoginseng at different concentrations. Results : Notoginseng significantly decreased LPS-induced production of $TNF-{\alpha}$ and IL-6 by the cultured microglial cells in a dose-dependent manner. The activation of iNOS mRNA and secretion of nitric oxide(NO) in microglial cells were inhibited in microglial cells in a dose-dependent manner by notoginseng. Conclusion : These results indicate that notoginseng inhibits LPS-induced activation of microglial cells and demonstrates notoginseng possess anti-inflammatory and immunosuppressive properties in vitro.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.3
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• pp.219-228
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• 2015

Excessive microglial activation and subsequent neuroinflammation lead to synaptic loss and dysfunction as well as neuronal cell death, which are involved in the pathogenesis and progression of several neurodegenerative diseases. Thus, the regulation of microglial activation has been evaluated as effective therapeutic strategies. Although dieckol (DEK), one of the phlorotannins isolated from marine brown alga Ecklonia cava, has been previously reported to inhibit microglial activation, the molecular mechanism is still unclear. Therefore, we investigated here molecular mechanism of DEK via extracellular signal-regulated kinase (ERK), Akt and nicotinamide adenine dinuclelotide phosphate (NADPH) oxidase-mediated pathways. In addition, the neuroprotective mechanism of DEK was investigated in microglia-mediated neurotoxicity models such as neuron-microglia co-culture and microglial conditioned media system. Our results demonstrated that treatment of anti-oxidant DEK potently suppressed phosphorylation of ERK in lipopolysaccharide (LPS, $1{\mu}g/ml$)-stimulated BV-2 microglia. In addition, DEK markedly attenuated Akt phosphorylation and increased expression of $gp91^{phox}$, which is the catalytic component of NADPH oxidase complex responsible for microglial reactive oxygen species (ROS) generation. Finally, DEK significantly attenuated neuronal cell death that is induced by treatment of microglial conditioned media containing neurotoxic secretary molecules. These neuroprotective effects of DEK were also confirmed in a neuron-microglia co-culture system using enhanced green fluorescent protein (EGFP)-transfected B35 neuroblastoma cell line. Taken together, these results suggest that DEK suppresses excessive microglial activation and microglia-mediated neuronal cell death via downregulation of ERK, Akt and NADPH oxidase-mediated pathways.

• 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.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.51-59
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• 2023

Background: This study investigated the effect of an excess and a deficit of spinal 5-hydroxytryptamine (5-HT) on the mechanical allodynia and neuroglia activation in a rodent pain model of carrageenan inflammation. Methods: Male Sprague-Dawley rats were implanted with an intrathecal (i.t.) catheter to administer the drug. To induce an excess or deficit of 5-HT in the spinal cord, animals were given either three i.t. 5-HT injections at 24-hour intervals or a single i.t. injection of 5,7-dihydroxytryptamine (5,7-DHT) before carrageenan inflammation. Mechanical allodynia was measured using the von Frey test for 0-4 hours (early phase) and 24-28 hours (late phase) after carrageenan injection. The changes in the activation of microglia and astrocyte were examined using immunofluorescence of the dorsal horn of the lumbar spinal cord. Results: Both an excess and a deficit of spinal 5-HT had no or a minimal effect on the intensity of mechanical allodynia during the early phase but prevented the attenuation of mechanical allodynia during the late phase, which was observed in animals not treated with i.t. 5-HT or 5,7-DHT. Animals with an excess or deficit of 5-HT showed stronger activation of microglia, but not astrocyte, during the early and late phases, than did normal animals. Conclusions: Imbalance in the descending 5-HT pathway in the spinal cord could aggravate the mechanical allodynia and enhance the activation of microglia, suggesting that the spinal 5-HT pathway plays an essential role in maintaining the nociceptive processing in balance between facilitation and inhibition in inflammatory pain caused by carrageenan inflammation.

• Archives of Pharmacal Research
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• v.27 no.9
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• pp.954-960
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• 2004

Expression of the NF-$textsc{k}$B-dependent genes responsible for inflammation, such as TNF-$\alpha$, IL-1$\beta$, and nitric oxide synthase (NOS), contributes to chronic inflammation which is a major cause of neurodegenerative diseases (i.e. Alzheimer＇s disease). Although NF-$textsc{k}$B plays a biphasic role in different cells like neurons and microglia, controlling the activation of NF-$textsc{k}$B is important for its negative feedback in either activation or inactivation. In this study, we found that ursodeoxycholic acid (UDCA) inhibited I$textsc{k}$B$\alpha$ degradation to block expression of the NF-$textsc{k}$B-dependent genes in microglia when activated by $\beta$-amyloid peptide (A$\beta$). We also showed that when microglia is activated by $A\beta$42, the expression of A20 is suppressed. These findings place A20 in the category of ' protective ' genes, protecting cells from pro-inflammatory reper-toires induced in response to inflammatory stimuli in activated microglia via NF-$textsc{k}$B activation. In light of the gene and proteins for NF-$textsc{k}$B-dependent gene and inactivator for NF-$textsc{k}$B (I$textsc{k}$B$\alpha$), the observations now reported suggest that UDCA plays a role in supporting the attenuation of the production of pro-inflammatory cytokines and NO via inactivation of NF-$textsc{k}$B. Moreover, an NF-$textsc{k}$B inhibitor such as A20 can collaborate and at least enhance the anti-inflammatory effect in microglia, thus giving a potent benefit for the treatment of neurodegenerative diseases such as AD.uch as AD.

• Journal of Life Science
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• v.33 no.5
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• pp.429-435
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• 2023

Epidemiological studies suggest that maternal infection, maternal stress, and environmental risk factors during pregnancy increase the risk of brain development abnormalities associated with cognitive impairment in the offspring and increase susceptibility to schizophrenia and autism spectrum disorder. Several animal models have demonstrated that maternal immune activation (MIA) is sufficient to induce abnormal brain development and behavioral defects in the fetus. When polyinosine:polycytodylic acid (poly I:C) or lipopolysaccharide (LPS), which is commonly used in maternal immune activation animal models, was introduced into a pregnant dam, an increase in pro-inflammatory cytokines and microglial activity was observed in the offspring's brain. Microglia are brain-resident immune cells that play a mediating role in the central nervous system, and they are responsible for various functions, such as phagocytosis, synapse formation and branching, and angiogenesis. Several studies have reported that microglia are activated in MIA offspring and influence offspring behavior through interactions with various cytokines. In addition, it has been reported that they play an important role in brain circuits through interactions with neurons and astrocytes. However, there is controversy concerning whether microglia are essential to brain development or lead to behavioral defects, and the exact mechanism remains unknown. Therefore, for the potential diagnosis and treatment of brain developmental disorders, a functional study of microglia should be conducted using MIA animal models.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.204.2-205
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• 2003

Microglial cell is a monocyte involved in the brain, which acts for a primary immune reaction and phagocytosis. Microglia has also been considered to have a great role in AD pathogenesis due to its intact inflammatory and phagocytic responses against foreign invaders. In the study, we tried to investigate the modulation of activation of microglia using Rg1, a class of ginsenoside from red ginseng. which are known to protect neuron cells. (omitted)

• Proceedings of the PSK Conference
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• 2003.10a
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• pp.106-107
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• 2003

tIn brain ischemic insult, inflammatory cells such as macrophages and lymphocytes are chemo-attracted into the brain lesion and release cytokines, resulting in an activation of microglia that are functionally equivalent to peripheral macrophages in the central nervous system. In cerebral ischemic insults, activated inflammatory cells such as microglia and macrophages may be implicated in the pattern and degree of ischemic injury by producing various bioactive mediators. (omitted)

• International Journal of Oral Biology
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• v.42 no.1
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• pp.9-15
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• 2017

Microglia have multiple functions in regulating homeostasis of the central nervous system. Microglia cells have been implicated as active contributors to neuron damage in neurodegenerative disorders. In this study, medicinal plant extracts (MPEs) were used to evaluate the cell-death induction effect in microglia BV-2 cells. Among 35 MPEs tested in this study, 4 MPEs showed less than a 30% cell survival after 24 hours of incubation. These were Foeniculi Fructus, Forsythiae Fructus, Zingiberis Rhizoma and Hedera Rhombea. The concentration showed that 50% cell death ($IC_{50}$) occurred with 33, 83, 67 Ed highlight: Please confirm wording, and $81{\mu}/ml$, respectively. For further study, we chose Zingiberis Rhizoma (ZR) which showed a reasonably low $IC_{50}$ value and an induction of cell death in a relatively narrow range. Western blot analysis showed that ZR-treated cells showed activation of caspase-3 and cleavage of PARP Ed highlight: When an acronym is first presented it needs to be spelled out in both dose- and time-dependent manners. However, the level of Bcl-2 and Bax were not changed by ZR-treatment in BV-2 cells. These results suggest that ZR-induced apoptosis in BV-2 cells occured through caspase-3 activation. The results also suggested that ZR may be useful in developing treatments for neurodegenerative diseases.