• Journal of Ginseng Research
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• v.47 no.3
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• pp.390-399
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• 2023

Background: Gintonin (GT), a Panax ginseng-derived lysophosphatidic acid receptor (LPAR) ligand, has positive effects in cultured or animal models for Parkinson's disease, Huntington's disease, and so on. However, the potential therapeutic value of GT in treating epilepsy has not yet been reported. Methods: Effects of GT on epileptic seizure (seizure) in kainic acid [KA, 55mg/kg, intraperitoneal (i.p.)]-induced model of mice, excitotoxic (hippocampal) cell death in KA [0.2 ㎍, intracerebroventricular (i.c.v.)]-induced model of mice, and levels of proinflammatory mediators in lipopolysaccharide (LPS)-induced BV2 cells were investigated. Results: An i.p. injection of KA into mice produced typical seizure. However, it was significantly alleviated by oral administration of GT in a dose-dependent manner. An i.c.v. injection of KA produced typical hippocampal cell death, whereas it was significantly ameliorated by administration of GT, which was related to reduced levels of neuroglial (microglia and astrocyte) activation and proinflammatory cytokines/enzymes expression as well as increased level of the Nrf2-antioxidant response via the upregulation of LPAR 1/3 in the hippocampus. However, these positive effects of GT were neutralized by an i.p. injection of Ki16425, an antagonist of LPA1-3. GT also reduced protein expression level of inducible nitric-oxide synthase, a representative proinflammatory enzyme, in LPS-induced BV2 cells. Treatment with conditioned medium clearly reduced cultured HT-22 cell death. Conclusion: Taken together, these results suggest that GT may suppress KA-induced seizures and excitotoxic events in the hippocampus through its anti-inflammatory and antioxidant activities by activating LPA signaling. Thus, GT has a therapeutic potential to treat epilepsy.

• Journal of Oriental Neuropsychiatry
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• v.18 no.2
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• pp.101-132
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• 2007

Objective : This research investigates the effect of the NogYongDaeBoTang,(NYDBT) on Alzheimer's disease. Method : The effects of the NYDBT extract on (1) $IL-1{\beta}$, IL-6, and $TNF-{\alpha}$ mRNA of PC-12 cells treated with LPS; (2) acetylcholinesterase(AChE), amyloid precursor proteins(APP), and glial fibrillary acidic protein(GFAP) mRNA the AChE activity and the APP production of PC-12 cell treated with CT-105; (3) the behavior; (4) expression of $IL-1{\beta}$, $TNF-{\alpha}$, MDA, $IL-1{\beta}$ mRNA, and $TNF-{\alpha}$ mRNA; (5) the infarction area of the hippocampus, and brain tissue injury in Alzheimer‘s diseased mice induced with ${\beta}A$ were investigated. Results : 1. The NYDBT extract suppressed the expression of $IL-1{\beta}$, IL-6 and $TNF-{\alpha}$ mRNA in BV2 microglia cell line treated with LPS. 2. The NYDBT extract suppressed the expression of $IL-1{\beta}$, IL-6, and $TNF-{\alpha}$ protein production in BV2 microglia cell line treated with LPS. 3. For the NYDBT extract group a significant inhibitory effect on the memory deficit was shown for the mice with Alzheimer's disease induced by $A{\beta}$ in the Morris water maze experiment, which measured stop-through latency, and distance movement-through latency. 4. The NYDBT extract suppressed the over-expression of $IL-1{\beta}$ protein, $TNF-{\alpha}$ protein, MDA, and CD68/CD11b, in the mice with Alzheimer's disease induced by $A{\beta}$. 5. The NYDBT extract reduced the infarction area of hippocampus, and controlled the injury of brain tissue in the mice with Alzheimer's disease induced by $A{\beta}$. 6. The NYDBT extract reduced the Tau protein, GFAP protein, and presenilin1/2 protein (immunohistochemistry) of hippocampus in the mice with Alzheimer's disease induced by $A{\beta}$. Conclusions : These results suggest that the NYDBT extract may be effective for the prevention and treatment of Alzheimer's disease.

• Biomolecules & Therapeutics
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• v.22 no.1
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• pp.17-26
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• 2014

${\alpha}$-Asarone exhibits a number of pharmacological actions including neuroprotective, anti-oxidative, anticonvulsive, and cognitive enhancing action. The present study investigated the effects of ${\alpha}$-asarone on pro-inflammatory cytokines mRNA, microglial activation, and neuronal damage in the hippocampus and on learning and memory deficits in systemic lipopolysaccharide (LPS)-treated C57BL/6 mice. Varying doses of ${\alpha}$-asarone was orally administered (7.5, 15, or 30 mg/kg) once a day for 3 days before the LPS (3 mg/kg) injection. ${\alpha}$-Asarone significantly reduced TNF-${\alpha}$ and IL-$1{\beta}$ mRNA at 4 and 24 hours after the LPS injection at dose of 30 mg/kg. At 24 hours after the LPS injection, the loss of CA1 neurons, the increase of TUNEL-labeled cells, and the up-regulation of BACE1 expression in the hippocampus were attenuated by 30 mg/kg of ${\alpha}$-asarone treatment. ${\alpha}$-Asarone significantly reduced Iba1 protein expression in the hippocampal tissue at a dose of 30 mg/kg. ${\alpha}$-Asarone did not reduce the number of Iba1-expressing microglia on immunohistochemistry but the average cell size and percentage areas of Iba1-expressing microglia in the hippocampus were significantly decreased by 30 mg/kg of ${\alpha}$-asarone treatment. In the Morris water maze test, ${\alpha}$-asarone significantly prolonged the swimming time spent in the target and peri-target zones. ${\alpha}$-Asarone also significantly increased the number of target heading and memory score in the Morris water maze. The results suggest that inhibition of pro-inflammatory cytokines and microglial activation in the hippocampus by ${\alpha}$-asarone may be one of the mechanisms for the ${\alpha}$-asarone-mediated ameliorating effect on memory deficits.

• Journal of Ginseng Research
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• v.44 no.5
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• pp.704-716
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• 2020

Background: Ginsenoside Rh2 (GRh2) is a characterized component in red ginseng widely used in Korea and China. GRh2 exhibits a wide range of pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer properties. However, its effects on Toxoplasma gondii (T. gondii) infection have not been clarified yet. Methods: The effect of GRh2 against T. gondii was assessed under in vitro and in vivo experiments. The BV2 cells were infected with tachyzoites of T. gondii RH strain, and the effects of GRh2 were evaluated by MTT assay, morphological observations, immunofluorescence staining, a trypan blue exclusion assay, reverse transcription PCR, and Western blot analyses. The in vivo experiment was conducted with BALB/c mice inoculated with lethal amounts of tachyzoites with or without GRh2 treatment. Results and conclusion: The GRh2 treatment significantly inhibited the proliferation of T. gondii under in vitro and in vivo studies. Furthermore, GRh2 blocked the activation of microglia and specifically decreased the release of inflammatory mediators in response to T. gondii infection through TLR4/NF-κB signaling pathway. In mice, GRh2 conferred modest protection from a lethal dose of T. gondii. After the treatment, the proliferation of tachyzoites in the peritoneal cavity of infected mice markedly decreased. Moreover, GRh2 also significantly decreased the T. gondii burden in mouse brain tissues. These findings indicate that GRh2 exhibits an antieT. gondii effect and inhibits the microglial activation through TLR4/NF-κB signaling pathway, providing the basic pharmacological basis for the development of new drugs to treat toxoplasmic encephalitis.

• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.321-330
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• 2021

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H2O2-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.

• Korean journal of applied entomology
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• v.45 no.1 s.142
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• pp.31-36
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• 2006

Inflammation in the brain has known to be associated with the development of a various neurologiacal diseases. The hallmark of neuro-inflammation is the activation of microglia, brain macrophage. Pro-inflammatory compounds including nitric oxide(NO) are the main cause of neuro-degenerative disease such as Alzheimer's disease. In the study, we examined whether Harmonia axyridis extracts inhibit the NO production by a direct method using Griess reagent, western blotting and by RT-PCR(Reverse Transcription-Polymerase Chain Reactionin) the gene expression of inducible nitric oxide synthase(iNOS). Distilled water$(H_2O)$ and methanol(MeOH) extracts of H. axyridis inhibited the protein expression of TNF-a(Tumor Necrosis Factor) and IL-6(Interleukin) in LPS (Lipopolysaccharide) stimulated BV-2 cells at the concentration of 100 ng/ml. Incubation of BV-2 cells with the extracts of $H_2O$ of MeOH inhibited the LPS induced NO and iNOS protein. And this inhibition of iNOS protein is concordant with the inhibition of iNOS mRNA expression. These data suggested that H. axyridis extracts may play a crucial role in inhibiting the NO production.

• Korean Journal of Pharmacognosy
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• v.47 no.1
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• pp.7-11
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• 2016

The aerial part of Trichosanthes kirilowii Maxim. (Cucurbitaceae), has long been used in traditional Korean and Chinese medicines for the treatment of heatstroke. We isolated and identified three flavones, luteolin-7-O-${\beta}$-D-glucopyranoside(1), luteolin-4'-O-${\beta}$-D-glucopyranoside(2), luteolin(3) from its methanolic extract. In the present study, we found that luteolin attenuates the lipopolysaccharide(LPS)-induced inflammation in BV2 microglial cells. Luteolin significantly inhibited LPS-induced production of pro-inflammatory mediators such as nitric oxide(NO) and prostaglandin $E_2(PGE_2)$ in BV2 microglia in a concentration-dependent manner without cytotoxic effect. Luteolin dose-dependently suppressed the protein expression of inducible nitric oxide synthase(iNOS) and cyclooxygenase-2(COX-2). In addition, luteolin also showed significant induction of heme oxygenase(HO)-1. These results suggest that both the aerial part of T. kirilowii and luteolin may be good candidates to regulate LPS-induced inflammatory response.

• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.8.1-8.14
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• 2018

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.1
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• pp.81-88
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• 2020

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, realtime reverse transcriptase-polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.

• Biomedical Science Letters
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• v.10 no.4
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• pp.325-332
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• 2004

Inflammatory factor such as Interleukin-1 play important roles in determining the fate of both acute and chronic neurological disorders. We investigated whether inhibitors of PKC or PTK can serve as pharmacological agents to reduce IL-I production and the mechanisms underlying their pharmacological effects in a mixed population of glia. Inhibitors of PKC such as H7, Go6976 and Ro31-8220 significantly reduced both the mRNA and protein levels of IL-1α and IL-β in lipopolysaccharide-activated primary glial cells. While the PTK inhibitor genistein also significantly reduced the production of these cytokines, it did not affect the expression of their mRNA. Taken together, inhibitors of PKC and PTK could serve as pharmacological agents to reduce IL-1 production. However, the mechanisms underlying their pharmacological effects are different. Our results provide evidence that inhibitors of protein kinases can serve as pharmacological agents to modulate IL-1 production in glial cell, and in turn, alleviate neuronal injury.