• The Korea Journal of Herbology
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• v.36 no.6
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• pp.1-8
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• 2021

Objectives : Atractylodis rhizoma Alba has been traditionally used as a medicinal resource that is used for enhancing Qi (氣) in traditional medicine in Korea, China, and Japan. This study investigated the protective effects of Atractylodis rhizoma Alba extract (ARE) against trimethyltin (TMT), a neurotoxin that causes selective hippocampal injury, using both in vitro and in vivo models. Methods : We investigated the effects of ARE on TMT- (5mM) induced cytotoxicity in primary cultures of mouse hippocampal cells (7 days in vitro ) and on hippocampal injury in C57BL/6 mice injected with TMT (2.6 mg/kg). Results : We observed that ARE treatment (0 - 50 ㎍/mL) significantly reduced TMT-induced cytotoxicity in cultured hippocampal neurons in a dose-dependent manner, based on results of lactate dehydrogenase and 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assays. Additionally, this study showed that orally administered ARE (5 mg/kg; between -6 and 0 days before TMT injection) significantly attenuated seizures in adult mice. Furthermore, quantitative analysis of allograft inflammatory factor-1 (Iba-1)- and glial fibrillary acidic protein (GFAP)- positive cells showed significantly reduced levels of Iba-1- and GFAP-positive cell bodies in the dentate gyrus of mice treated with ARE prior to TMT injection. These findings indicate the significant protective effects of ARE against the TMT-induced massive activation of microglia and astrocytes in the hippocampus. Conclusions : We conclude that ARE minimizes the detrimental effects of TMT-induced hippocampal neurotoxicity, both in vitro and in vivo . Our findings may serve as useful guidelines to support ARE administration as a promising pharmacotherapeutic approach to hippocampal degeneration.

• 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.21 no.1
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• pp.109-124
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• 2010

Objectives: This experiment was designed to investigate the effect of the InSamYangYoung-tang(Renshenyangrongtang) extract on $A{\beta}$-induced AD model. Methods: The effects of the InSamYangYoung-tang(Renshenyangrongtang) extract on neural damages of cultured PC12 cells induced by $A{\beta}$ were investigated. The effects of the InSamYangYoung-tang(Renshenyangrongtang) extract on neural damages of hippocampal and cortical neurons in the mouse induced by $\beta$-amyloid were investigated. Results: 1. $A{\beta}$ treatment into neuronal cells activated cell death pathway when analyzed by MTT assay and by histological analysis. Then InSamYangYoung-tang(Renshenyangrongtang) treatment improved cell survival to a similar level as in normal group. 2. $A{\beta}$ treatment increased caspase 3 protein levels but decreased phospho-Erk1/2 in neuronal cells. InSamYangYoung-tang(Renshenyangrongtang) treatment reversed the production levels of two proteins close to those in normal group. 3. $A{\beta}$ treatment induced the atrophy of neuronal cells in terms of neuronal processes and cell body shrinkage, but InSamYangYoung-tang(Renshenyangrongtang) greatly improved their morphology. 4. Neuroprotective activity, as observed in InSamYangYoung-tang(Renshenyangrongtang)-treated groups, was similarly observed in cells treated with galantamine which was used as a positive control. Moreover, overall recovery pattern by InSamYangYoung-tang(Renshenyangrongtang) was similar between cultured PC12 cells and in vivo hippocampal and cerebral cortical neurons in the mouse brain. Conclusions: This experiment shows that the InSamYangYoung-tang(Renshenyangrongtang) may play a protective role in neural tissues damaged by cytotoxic substances. Since neuronal damage seen in degenerative brains such as AD are largely unknown, the current data may provide possible insight into therapeutic strategies for AD treatments. InSamYangYoung-tang(Renshenyangrongtang) might be effective for the treatment of AD. Investigation into the clinical use of the InSamYangYoung-tang(Renshenyangrongtang) for AD is suggested for future research.

• Journal of Physiology & Pathology in Korean Medicine
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• v.19 no.3
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• pp.647-655
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• 2005

This study demonstrated anti-oxidative and neuroprotective effects of Rhei Rhizoma. Anti-oxidative effects were studied on BV-2 microglia cells damaged by $H_2O_2$ and nitric oxide. Neuroprotective effects were studied by using oxygen/glucose deprivation of the organotypic hippocampal slice cultures. The results obtained are as follows; The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of neuronal cell death area and cell death area percentages in CA1 region of ischemic damaged hippocampus cultures during whole 48 hours of the experiment. The group treated with 50 mg/ml of Puerariae Radix demonstrated decreases of neuronal cell death area and cell death area percentages in CA1 region, but these were not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of neuronal cell death area and cell death area percentages in dentate gyrus of ischemic damaged hippocampus cultures during whole 48 hours of the experiment. The group treated with 50 mg/ml of Puerariae Radix demonstrated decreases of neuronal cell death area and cell death area percentages in dentate gyrus, but these were not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of TUNEL-positive cells in both CA1 region and dentate gyrus of ischemic damaged hippocampus cultures. The group treated with 50 mg/ml of Puerariae Radix demonstrated significant decrease of TUNEL-positive cells in CA1 region, but not in dentate gyrus of ischemic damaged hippocampus. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant decreases of LDH concentrations in culture media of ischemic damaged hippocampus cultures. The group treated with 50 mg/ml of Puerariae Radix demonstrated decrease of LDH concentrations in culture media, but it was not significant statistically. The groups treated with 0.5 and 5 mg/ml of Puerariae Radix revealed significant increases of cell viabilities of BV-2 microglia cells damaged by $H_2O_2$. The group treated with 50 mg/ml of Puerariae Radix demonstrated increase of cell viability of BV-2 microglia cells, but it was not significant statistically. The group treated with 0.5 mg/ml of Puerariae Radix revealed significant increase of cell viability of BV-2 microglia cells damaged by nitric oxide. The groups treated with 5 and 50 mg/ml of Puerariae Radix demonstrated increases of cell viabilities of BV-2 microglia cells, but these were not significant statistically. These results suggested that Puerariae Radix revealed neuroprotective effects through the control effect of apoptosis and oxidative damages.

• Journal of Life Science
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• v.17 no.3 s.83
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• pp.305-311
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• 2007

Glucocorticoids (GCs) alter metabolism, synaptogenesis, apoptosis, neurogenesis, and dendritic morphology in the hippocampus. To better understand how glucocorticoids regulate these aspects of hippocampal biology, we studied gene expression patterns in the CA3 (Hippocampal pyramidal cell field CA3) and dentate gyrus (DG). Litter-matched Lewis inbred rats treated for 20 days with either 9.5 mg per day sustained-release corticosterone or placebo pellets were compared with high-density oligonucleotide microarray analysis (Rat Neurobiology U34 Arrays, Affymetrix). In placebo-treated rats, 32 genes were expressed at greater levels in CA3 than DG, whereas 3 genes were expressed at great levels in DC than CA3. Regional differences were also apparent in corticosterone-induced changes in the hippocampal transcriptome. Six genes in CA3 and 41 genes in DC were differentially regulated by corticosterone. As per the glucocorticoid effects on gene transcription in the brain, forty three of these genes were upregulated, and 4 genes were downregulated. Genes differentially expressed in hippocampus included those for 13 neurotransmitter proteins, 5 ion channel related proteins, 4 transcription factors, 3 neurotrophic factors, 1 cytokine, 1 apoptosis related protein, and 5 genes involved in synaptogenesis. Interestingly, GCs can have suppressive effects on brain BDNF mRNA transcription, one of the neurotrophic factors. These results indicate the diversity of targets affected by chronic exposure to corticosterone and highlight important regional differences in hippocampal neurobiology.

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.3-19
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• 2001

Recent basic and clinical studies demonstrate a major role for neural plasticity in the etiology and treatment of depression and stress-related illness. The neural plasticity is reflected both in the birth of new cell in the adult brain(neurogenesis) and the death of genetically healthy cells(apoptosis) in the response to the individual's interaction with the environment. The neural plasticity includes adaptations of intracellular signal transduction pathway and gene expression, as well as alterations in neuronal morphology and cell survival. At the cellular level, repeated stress causes shortening and debranching of dendrite in the CA3 region of hippocampus and suppress neurogenesis of dentate gyrus granule neurons. At the molecular level, both form of structural remodeling appear to be mediated by glucocorticoid hormone working in concert with glutamate and N-methyl-D-aspartate(NMDA) receptor, along with transmitters such as serotonin and GABA-benzodiazepine system. In addition, the decreased expression and reduced level of brain-derived neurotrophic factor(BDNF) could contribute the atrophy and decreased function of stress-vulnerable hippocampal neurons. It is also suggested that atrophy and death of neurons in the hippocampus, as well as prefrontal cortex and possibly other regions, could contribute to the pathophysiology of depression. Antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function via up-regulation of cyclic adenosine monophosphate response element-binding proteins(CREB) and BDNF. In this article, the molecular and cellular mechanisms that underlie stress, depression, and action of antidepressant are precisely discussed.

• The Journal of Internal Korean Medicine
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• v.25 no.4
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• pp.227-241
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• 2004

Objective : This study was performed to investigate neuroprotective effects of Bupleuri Radix against oxidative and ischemic damages. Method : To observe the neuroprotective effects against ischemic damage, ischemic insult was induced by oxygen/glucose deprivation (OGD) on organotypic hippocampal slice cultures (OHSC) from 1 week-old Sprague-Dawley rats. Propidium iodide (PI) fluorescence-stained neuronal dead-cell areas, area percentages and TUNEL-positive apoptotic cells in CA1 and dentate gyrus, and LDH levels in culture media of the OHSC were measured following Bupleuri Radix extract treatment. Result : The following results were obtained: (1) The $5\;{\mu}g/ml$ of Bupleuri Radix treatment demonstrated a significant decrease in PI fluorescence-stained neuronal dead-cell areas and area percentage in CA1 region of the OHSC from 18 hrs to 48 hrs following the OGD. The $50\;{\mu}g/ml$ of Bupleuri Radix treatment was also significant from 6 hrs to 48 hrs following the OGD and was more effective. (2) The 5 and $50\;{\mu}g/ml$ of Bupleuri Radix treatment demonstrated a significant decrease in PI fluorescence-stained neuronal dead-cell areas and area percentage in DG region of the OHSC from 6 hrs to 48 hrs following the OGD. The $50\;{\mu}g/ml$ treatment was more effective than the $5\;{\mu}g/ml$ treatment. (3) Bupleuri Radix treatment demonstrated a significant decrease in TUNEL-positive apoptotic cells in CA1 region (with 5 and $50\;{\mu}g/ml$) and in DG region (with $50\;{\mu}g/ml$) of the OHSC damaged by the OGD. (4) Bupleuri Radix treatment demonstrated a significant decrease in LDH concentrations in culture media of the OHSC damaged by the OGD. Conclusion : These results suggest that Bupleuri Radix has neuroprotective and control effects on inflammatory and immune responses where there has been ischemic damage to the central nervous system.

• BMB Reports
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• v.35 no.1
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• pp.87-93
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• 2002

Neural cell survival is an essential concern in the aging brain and many diseases of the central nervous system. Neural transplantation of the stem cells are already applied to clinical trials for many degenerative neurological diseases, including Huntington's disease, Parkinson's disease, and strokes. A critical problem of the neural transplantation is how to reduce their apoptosis and improve cell survival. Neurotrophic factors generally contribute as extrinsic cues to promote cell survival of specific neurons in the developing mammalian brains, but the survival factor for neural stem cell is poorly defined. To understand the mechanism controlling stem cell death and improve cell survival of the transplanted stem cells, we investigated the effect of plausible neurotrophic factors on stem cell survival. The neural stem cell, HiB5, when treated with PDGF prior to transplantation, survived better than cells without PDGF. The resulting survival rate was two fold for four weeks and up to three fold for twelve weeks. When transplanted into dorsal hippocampus, they migrated along hippocampal alveus and integrated into pyramidal cell layers and dentate granule cell layers in an inside out sequence, which is perhaps the endogenous pathway that is similar to that in embryonic neurogenesis. Promotion of the long term-survival and differentiation of the transplanted neural precursors by PDGF may facilitate regeneration in the aging adult brain and probably in the injury sites of the brain.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.127-138
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• 2023

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (Tau_RD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC₅₀ of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 Tau_RD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 Tau_RD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 Tau_RD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.2
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• pp.135-141
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• 2014

The downregulation of A-type $K^+$ channels ($I_A$ channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As $I_A$ channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic $I_A$ channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of $I_A$ recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the $I_A$ peak, indicating the necessity of synaptic activation for the reduction of somatic $I_A$. This was again confirmed by glycine treatment, showing a significant reduction of the somatic $I_A$ peak. Additionally, the gating property of $I_A$ channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating $I_A$ channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.