• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• 제33권3호
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• pp.227-237
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• 2007

Microglial cell activation is known to contribute to neuropathic pain following spinal sensory nerve injuries. In this study, I investigated its mechanisms in the case of trigeminal sensory nerve injuries by which microglial cell and p38 mitogen-activated protein kinase (p38 MAPK) activation in the medullary dorsal horn (MDH) would contribute to the facial pain hypersensitivity following mandibular nerve transection (MNT). And also investigated the changes of trigeminal ganglion neurons and ERK, p38 MAPK manifestations. Activation of microglial cells was monitored at 1, 3, 7, 14, 28 and 60 day using immunohistochemical analyses. Microglial cell activation was primarily observed in the superficial laminae of the MDH. Microglial cell activation was initiated at postoperative 1 day, maximal at 3 day, maintained until 14 day and gradually reduced and returned to the basal level by 60 days after MNT. Pain hypersensitivity was also initiated and attenuated almost in parallel with microglial cell activation pattern. To investigate the contribution of the microglial cell activation to the pain hypersensitivity, minocycline, an inhibitor of microglial cell activation by means of p38 MAPK inhibition, was administered. Minocycline dose-dependently attenuated the development of the pain hypersensitivity in parallel with inhibition of microglial cell and p38 MAPK activation following MNT. Mandibular nerve transection induced the activation of ERK, but did not p38 MAPK in the trigeminal ganglion. These results suggest that microglial cell activation in the MDH and p38 MAPK activation in the hyperactive microglial cells play an important role in the development of facial neuropathic pain following MNT. The results also suggest that ERK activation in the trigeminal ganglion contributes microglial cell activation and facial neuropathic pain.

• Genomics & Informatics
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• 제21권1호
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• pp.2.1-2.14
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• 2023

Microglia, similar to peripheral macrophages, are the primary immune cells of the central nervous system (CNS). Microglia exist in the resting state in the healthy CNS, but can be activated and polarized into either M1 or M2 subtypes for immune defense and the maintenance of CNS homeostasis by multiple stimuli. Several long noncoding RNAs (lncRNAs) mediate human inflammatory diseases and neuropathologies by regulating their target genes. However, the function of common lncRNAs that contribute to microglial activation remains unclear. Thus, we used bioinformatic approaches to identify common lncRNAs involved in microglial activation in vitro. Our study identified several lncRNAs as common regulators of microglial activation. We identified 283 common mRNAs and 53 common lncRNAs during mouse M1 microglial activation processes, whereas 26 common mRNAs and five common lncRNAs were identified during mouse M2 microglial activation processes. A total of 648 common mRNAs and 274 common lncRNAs were identified during the activation of human M1 microglia. In addition, we identified 1,920 common co-expressed pairs in mouse M1 activation processes and 25 common co-expressed pairs in mouse M2 activation processes. Our study provides a comprehensive understanding of common lncRNA expression profiles in microglial activation processes in vitro. The list of common lncRNAs identified in this study provides novel evidence and clues regarding the molecular mechanisms underlying microglial activation.

• Biomolecules & Therapeutics
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• 제29권3호
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• pp.295-302
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• 2021

Microglial priming is the process of microglial proliferation and activation in response to neurodegeneration and abnormal protein accumulation. Priming makes microglia susceptible to secondary inflammatory stimuli and causes exaggerated inflammatory responses. In the present study, we established a microglial priming model in mice by administering a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg). MPTP induced microglial activation without dopaminergic degeneration; however, subsequent treatment with a sub-toxic dose of lipopolysaccharides (LPS) induced an amplified inflammatory response and caused nigrostriatal dopaminergic degeneration. These pathological and inflammatory changes, including microglial activation and dopaminergic cell loss in the substantia nigra (SN) area were reversed by papaverine (PAP) administration. In addition, MPTP/LPS enhanced interleukin-1β (IL-1β) expression and processing via nod-like receptor protein 3 (NLRP3) inflammasome activation in the SN region of mice. However, PAP treatment suppressed inflammasome activation and subsequent IL-1β maturation. Moreover, PAP inhibited nuclear factor-κB (NF-κB) and enhanced cAMP-response element binding protein (CREB) activity in the SN of MPTP/LPS mice. These results suggest that PAP inhibits the activation of NLRP3 inflammasome by modulating NF-κB and CREB signaling pathways, which results in reduced microglial activation and neuronal cell death. Thus, PAP may be a potential candidate for the treatment of Parkinsons's disease, which is aggravated by systemic inflammation.

• 약학회지
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• 제44권5호
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• pp.448-454
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• 2000

Microglia, brain resident macrophages, play a central role in the inflammatory responses of the brain and are activated in brain injuries and several neurodegenerative diseases such as Alzheimer's and Parkinson's disease, thereby aggravating the course of these diseases. In this study, the effects of plantderived compounds such as curcumin or gingerol on the microglial activation were examined. Microglial cultures were prepared from 2~3 week mixed primary glial cultures obtained from the cerebral cortex of 1~2 day old rats and identified by immunocytochemistry using microglial-specific antibody OX-42. Microglia were activated by lipopolysaccharide (LPS) and interferon-${\gamma}$ (IFN-${\gamma}$) and the effect of curcumin or 6-gingerol on the microglial activation was examined. Specific parameters measured to monitor microglial activation were nitric oxide (NO), prostaglandin E$_2$(PGE$_2$) and tumor necrosis factor-$\alpha$ (TNF-$\alpha$) release. Curcumin (1~10 $\mu$M) inhibited NO release induced by LPS and IFN-${\gamma}$ in a dose-dependent manner whereas 6-gingerol (2~20 $\mu$M) did not have any effect on LPS/IFN-${\gamma}$-induced NO release. The levels of PGE$_2$and TNF-$\alpha$ induced by LPS and IFN-${\gamma}$ were also inhibited by 1~10 $\mu$M curcumin in a dose-dependent manner. These results showed that curcumin could modulate microglial activation.

• BMB Reports
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• 제54권12호
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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.

• Biomolecules & Therapeutics
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• 제29권2호
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• pp.127-134
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• 2021

Neuroinflammation―a common pathological feature of neurodegenerative disorders such as Alzheimer's disease―is mediated by microglial activation. Thus, inhibiting microglial activation is vital for treating various neurological disorders. 7,3',4'-Trihydroxyisoflavone (THIF)―a secondary metabolite of the soybean compound daidzein―possesses antioxidant and anticancer properties. However, the effects of 7,3',4'-THIF on microglial activation have not been explored. In this study, antineuroinflammatory effects of 7,3',4'-THIF in lipopolysaccharide (LPS)-stimulated BV2 microglial cells were examined. 7,3',4'-THIF significantly suppressed the production of the proinflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) as well as of the proinflammatory cytokine interleukin-6 (IL-6) in LPS-stimulated BV2 microglial cells. Moreover, 7,3',4'-THIF markedly inhibited reactive oxygen species (ROS) generation. Western blotting revealed that 7,3',4'-THIF diminished LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β), and nuclear factor kappa B (NF-κB). Overall, 7,3',4'-THIF exerts antineuroinflammatory effects against LPS-induced microglial activation by suppressing mitogen-activated protein kinase (MAPK) and NF-κB signaling, ultimately reducing proinflammatory responses. Therefore, these antineuroinflammatory effects of 7,3',4'-THIF suggest its potential as a therapeutic agent for neurodegenerative disorders.

• 대한본초학회지
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• 제21권4호
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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.

• 대한본초학회지
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• 제28권2호
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• pp.1-7
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• 2013

Objectives : Sesamin, a major lignan in sesame seeds, has been reported to have neuroprotective effects against in vitro ischemia and in vivo MCAo-reperfusion cerebral ischemia model, however, there is no reports in an in vivo global cerebral ischemia model. The purpose of the study was to investigate the neuroprotective effect of sesamin in global cerebral ischemia induced by four-vessel occlusion (4-VO) in rats through inhibition of microglial activation in this model. Methods : The neuroprotective effects were investigated using a 10 min of 4-VO ischemia rat model by measuring intact pyramidal neurons in the CA1 region of the hippocampus using Nissle staining. The antiinflammatory or reducing neurotoxicity effect was investigated using immunohistochemisty, RT-PCR and western blot analysis of inflammatory or neurotoxic mediators. Results : Intraperitoneal injection of sesamin at doses of 0.3, 1.0, 3.0, and 10.0 mg/kg at 0 min and 90 min after ischemia conferred 26.6%, 30.1%, 42.5%, and 30.5% neuroprotection, respectively, compared to the vehicle-treated control group. A 3.0 mg/kg dose of sesamin inhibited microglia activation and consequently, cyclooxygenase-2, inducible nitric oxide, and interleukine-$1{\beta}$ expressions at 48 h after reperfusion. Conclusions : Sesamin protects neuronal cell death through inhibition of microglial activation or the production of neurotoxic metabolites and proinflammatory mediators by microglia such as COX-2, iNOS and IL-$1{\beta}$ in global cerebral ischemia.

• The Korean Journal of Physiology and Pharmacology
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• 제16권1호
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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.

• Korean Journal of Acupuncture
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• 제24권1호
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• pp.131-144
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• 2007

Objectives : Although the cause of neuronal death of Parkinson's disease remains unclear, increasing evidence points to the role of inflammatory processes. And the hallmark of brain inflammation is the activation of microglia. This study was performed to prove the effect of acupuncture on inhibiting microglial activation. Methods : The rat models which were injected with 6-hydroxydopamine were treated with acupuncture once a day on LR3 (太衝) and GB34 (陽陵泉). To prove the effect of inhibiting microglial activation, we examined the tyrosine hydroxylase (TH) immunopositive neurons and CD11b immunohistochemistry in the substantia nigra. Results : There were 18% (third day), 32% (seventh day) loss of TH-positive cell bodies in the control group and 23% (third day), 26% (seventh day) in the acupuncture group, whereas 3% (third day), 10% (seventh day) in vehicle group. The difference of optical density in substantia nigra was evaluated by subtracting log inverse gray value of contralateral side from that of ipsilateral side. With regards to the result of CD11b immunohistochemistry, acupuncture group showed significantly inhibited microglial activation compared with control group (p<0.01) on the seventh day. Conclusions : Acupuncture showed the effect of inhibition of microglial activation in seventh day. However, the effect of protection of TH positive cell bodies was not shown. So we need longer investigation of the effect of acupuncture on Parkinson's disease.