• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.597-603
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• 2015

Synthetic cannabinoids JWH-018 and JWH-250 in 'herbal incense' also called 'spice' were first introduced in many countries. Numerous synthetic cannabinoids with similar chemical structures emerged simultaneously and suddenly. Currently there are not sufficient data on their adverse effects including neurotoxicity. There are only anecdotal reports that suggest their toxicity. In the present study, we evaluated the neurotoxicity of two synthetic cannabinoids (JWH-081 and JWH-210) through observation of various behavioral changes and analysis of histopathological changes using experimental mice with various doses (0.1, 1, 5 mg/kg). In functional observation battery (FOB) test, animals treated with 5 mg/kg of JWH-081 or JWH-210 showed traction and tremor. Their locomotor activities and rotarod retention time were significantly (p<0.05) decreased. However, no significant change was observed in learning or memory function. In histopathological analysis, neural cells of the animals treated with the high dose (5 mg/kg) of JWH-081 or JWH-210 showed distorted nuclei and nucleus membranes in the core shell of nucleus accumbens, suggesting neurotoxicity. Our results suggest that JWH-081 and JWH-210 may be neurotoxic substances through changing neuronal cell damages, especially in the core shell part of nucleus accumbens. To confirm our findings, further studies are needed in the future.

• Journal of Preventive Medicine and Public Health
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• v.29 no.3 s.54
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• pp.657-668
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• 1996

To investigate the factors which affecting the cognitive impairment of the 60 or more age group, the authors surveyed for the subjects in some area of Kyungnam Province. 201 studied subjects were tested for cognitive function with mini-mental state examination(MMSE). Information on demographic characteristics and life style has been collected through direct interview. The concentration of Ai and Ca of subject's drinking water, which might be related with cognition, was measured by Inductively Coupled Argon Plasma Spectrometer. The main results were summarized as follows. 1. The prevalence rate of cognitive impairment was 18.4% in male and 45.2% in female and this sexual difference was statistically significant(p=0.03). And the uneducated or illiterated showed significantly high prevalence rate of cognitive impairment(p=0.02). 2. In stratified analysis by sex md education year, we can not see significant trend indicating the neurotoxic effects of aluminum and protective effects of calcium to the cognitive function(p>0.05). 3. The correlation between the concentration of aluminum in drinking water and the MMSE score in whole subjects showed weak negative relationship(r=-0.066). But there was no statistical significance(p=0.434).

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.4
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• pp.273-279
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• 2009

The accumulation of ${\beta}$-amyloid (A${\beta}$) aggregates is a characteristic of Alzheimer's disease (AD). Furthermore, these aggregates have neurotoxic effects on cells, and thus, molecules that inhibit A${\beta}$ aggregate formation could be valuable therapeutics for AD. It is well known that aggregation of A${\beta}$ depends on its hydrophobicity, and thus, in order to increase the hydrophilicity of A${\beta}$, we considered using citrate, an anionic surfactant with three carboxylic acid groups. We hypothesized that citrate could reduce hydrophobicity and increase hydrophilicity of A${\beta}_{1-40}$ molecules via hydrophilic/electrostatic interactions. We found that citrate significantly inhibited A${\beta}_{1-40}$ aggregation and significantly protected SH-SY5Y cell line against A${\beta}_{1-40}$ aggregates-induced neurotoxicity. In details, we examined the effects of citrate on A${\beta}_{1-40}$ aggregation and on A${\beta}_{1-40}$ aggregates-induced cytotoxicity, cell viability, and apoptosis. Th-T assays showed that citrate significantly inhibited A${\beta}_{1-40}$ aggregation in a concentration-dependent manner (Th-T intensity: from 91.3% in 0.01 mM citrate to 82.1% in 1.0 mM citrate vs. 100.0% in A${\beta}_{1-40}$ alone). In cytotoxicity and viability assays, citrate reduced the toxicity of A${\beta}_{1-40}$ in a concentration-dependent manner, in which the cytotoxicity decreased from 107.5 to 102.3% as compared with A${\beta}_{1-40}$ aggregates alone treated cells (127.3%) and the cell viability increased from 84.6 to 93.8% as compared with the A${\beta}_{1-40}$ aggregates alone treated cells (65.3%). Furthermore, Hoechst 33342 staining showed that citrate (1.0 mM) suppressed A${\beta}_{1-40}$ aggregates-induced apoptosis in the cells. This study suggests that citrate can inhibit A${\beta}_{1-40}$ aggregation and protect neurons from the apoptotic effects of A${\beta}_{1-40}$ aggregates. Accordingly, our findings suggest that citrate administration should be viewed as a novel neuroprotective strategy for AD.

• The Korean Journal of Pain
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• v.23 no.2
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• pp.116-123
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• 2010

Background: Pamidronate is a potent inhibitor of osteoclast-mediated bone resorption. Recently, the drug has been known to relieve bone pain. We hypothesized that direct epidural administration of pamidronate could have various advantages over oral administration with respect to dosage, side effects, and efficacy. Therefore, we evaluated the neuronal safety of epidurally-administered pamidronate. Methods: Twenty-seven rats weighing 250-350 g were equally divided into 3 groups. Each group received an epidural administration with either 0.3 ml (3.75 mg) of pamidronate (group P), 0.3 ml of 40% alcohol (group A), or 0.3 ml of normal saline (group N). A Pinch-toe test, motor function evaluation, and histopathologic examination of the spinal cord to detect conditions such as chromatolysis, meningeal inflammation, and neuritis, were performed on the 2nd, 7th, and 21st day following administration of each drug. Results: All rats in group A showed an abnormal response to the pinch-toe test and decreased motor function during the entire evaluation period. Abnormal histopathologic findings, including neuritis and meningeal inflammation were observed only in group A rats. Rats in group P, with the exception of 1, and group N showed no significant sensory/motor dysfunction over a 3-week observation period. No histopathologic changes were observed in groups P and N. Conclusions: Direct epidural injection of pamidronate (about 12.5 mg/kg) showed no neurotoxic evidence in terms of sensory/motor function evaluation and histopathologic examination.

• Korean Journal of Biological Psychiatry
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• v.11 no.2
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• pp.94-103
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• 2004

Objective:There have been a kind of transmethylation theory that high homocysteine serum concentration affects schizophrenia by neurotoxic mechanism and clinical reports that some schizophrenic patients with high homocysteine were improved by high folate ingestion. This study was done to confirm previous research results and find the clinical characteristics of schizophrenia showing high serum homocysteine and low folate. Method:We compared the serum levels of homocysteine, folate and vitamin B12 level between 234 schizophrenic patients(male 99, female 135) group and 234 normal controls(male 99, female 135) group. The subjects of two groups were age and sex matched. The evaluated clinical characteristics items were sex, age, onset of disease, hereditary loading, disease course, hallucination and subtype of schizophrenia. Results:1) Homocysteine level of the schizophrenia group was significantly higher than the normal control group and folate level of the schizophrenia group was significantly lower than the normal control group. Homocysteine level was more negatively correlated with folate level in the schizophrenia group than the normal control group. 2) The percentage of high homocysteine(above 12.46umol/L;90 percentile of normal control) was 33.8% of schizophrenia patients and 51.5% of male schizophrenia. The percentage of low folate(below 3.8nM/L;bottom tertile of normal control) was 66.2% of schizophrenia. 3) In low folate group and not-low folate group, schizophrenia showed significantly higher homocysteine level than normal control. Especially, low folate schizophrenia group showed significantly higher homocysteine level than low folate normal control group. Conclusions:Some schizophrenia patients with high serum homocysteine may be genetic defector and having low folate serum level. In that case, folate ingestion could be a good management for clinical improvement.

• Journal of Oriental Neuropsychiatry
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• v.23 no.1
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• pp.93-114
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• 2012

Objective : This study aimed to review the performance of traditional herbal prescriptions for treating dementia and present a strategy for research on dementia therapy utilizing herbal medicine. Methods : A definition was made to clarify the technology regarding the development of herbal prescriptions for treating dementia. The queries were compounded based on the initial keywords provided by experts in the field, then applied to the Web of Science database search engines from January 1986 to September 2011 to search related scientific articles. Before performing the analysis, papers were extracted from the initial search reviewed by experts and 80 articles were selected. Then, the selected papers were analyzed in terms of publish year, country, and type of herbal prescriptions. Furthermore, the research performance evaluation for treating dementia by herbal prescriptions was also created in terms of country and organization based on forward citation analysis. In addition to, for the evaluation regarding research quality, we classified and reviewed papers into two types: clinical studies and experimental studies. Results : According to the quantitative information analysis of 80 articles, the number of papers has increased by 21.9% per the yearly mean from 1995, and Japan had the largest portion within this research field. There were 34 kinds of traditional herbal prescriptions, among them Ukgansan had the highest number of studies followed by Jodeungsan, Dangkisoosan and so on. In addition, quality index as calculated by cites per paper is higher than average in Switzerland, Turkey and Japan. In the view of the evaluation on quality there were 12 clinical studies, 8 RCT reported that herbal prescriptions had efficacy at cognition, behavioral & psychological symptoms (BPSD) and activity of daily life (ADL) in various type of dementia. In experimental studies most of the studies were performed using animal models. The studies using Ukgansan were aimed at improving BPSD. The papers studied with Jodeungsan and Dangkisoosan targeted vascular dementia. Conclusions : In this study, research to develop traditional herbal prescriptions for treating dementia has the potential to improve symptoms since herbal medicines work as both multi-function and multi-target in dementia with multiple pathological or neurotoxic pathways. Therefore, the results of the research should be used in order to establish strategies to develop technology for treating dementia with traditional herbal prescriptions in the future.

• The Journal of Korean Medicine
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• v.30 no.4
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• pp.13-27
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• 2009

Objectives: Trans-cinnamaldehyde (TCA) is the main component of Cinnamomi Ramulus and it has been reported that TCA inhibits inflammatory responses in various cell types. Inflammation-mediated neurological disorders induce the activation of macrophages such as microglia in brain, and these activated macrophages release various inflammation-related molecules, which can be neurotoxic if overproduced. In this study, we evaluated gene expression profiles using gene chip microarrays in lipopolysaccharide (LPS)-stimulated BV-2 cells to investigate the antiinflammatory effect of TCA on inflammatory responses in brain microglia. Methods: A negative control group was cultured in normal medium and a positive control group was stimulated with $1{\mu}g/ml$ in the absence of TCA. TCA group was pretreated with $10{\mu}g/ml$ before $1{\mu}g/ml$ LPS stimulation. The oligonucleotide microarray analysis was performed to obtain the expression profiles of 28,853 genes using gene chip mouse gene 1.0 ST array in this study. Results: In positive control group, 1522 probe sets were up-regulated in the condition of the cutoff value of 1.5-fold change and 341 genes with Unigene ID were retrieved. In TCA group, 590 probe sets were down-regulated from among 1522 probe sets and 33 genes with Unigene ID were retrieved, which included 6 inflammation-related genes. We found out that Id3 gene is associated with transforming growth factor-${\beta}$ (TGF-${\beta}$) signaling pathway and Klra8 gene is related to natural killer cell-mediated cytotoxicity pathway. Conclusions: The results mean that TCA inhibits inflammatory responses through down-regulating the expressions of inflammation-related genes in LPS-stimulated BV-2 cells.

• Biomolecules & Therapeutics
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• v.17 no.1
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• pp.47-56
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• 2009

Schizandra chinensis (S. chinensis) exhibits a harmless, 'adaptogen-type' effect leading to improvements in mental performance and learning efficacy in brain. Activated microglia contributes to neuronal injury by releasing neurotoxic products, which make it important to regulate microglial activation to prevent further cytological as well as functional brain damage. However, the effect of S. chinensis on microglial activation has not been examined yet. We have investigated the effects of four compounds (Gomisin A, Gomisin N, Schizandrin and Schizandrol A) from S. chinensis on lipopolysaccharide (LPS)-induced microglial activation. In this study, BV2 microglial cells were activated with LPS and the microglial activation was assessed by up-regulation of activation markers such as nitric oxide (NO), reactive oxygen species (ROS), and matrix metalloproteinase-9 (MMP-9). The results showed that all four compounds significantly reduced the intracellular level of ROS, the release of NO and MMP-9 as well as LPS-induced phosphorylation of ERK1/2. These results strongly suggested that S. chinensis may be useful to modulate inflammation-mediated brain damage by regulating microglial activation.

• Toxicological Research
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• v.6 no.2
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• pp.205-213
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• 1990

The regulation of neurotoxicants has usually been based upon setting reference doses by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that theoretically account for interspecies and intraspecies extraploation of experimental results in animals to humans. Recently, we have proposed a four-step alternative procedure which provides quantitative estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect or biomarker and the dose of chemical administered. The second step is to determine the distribution (variability) of individual measurements of biological effects or their biomarkers about the dose response curve. The third step is to define an adverse or abnormal level of a biological effect or biomarker in an untreated population. The fourth and final step is to combine the information from the first three steps to estimate the risk (proportion of individuals exceeding on adverse or abnormal level of a biological effect or biomarker) as a function of dose. The primary purpose of this report is to enhance the certainty of the first step of this procedure by improving our understanding of the relationship between a biomarker and dose of administered chemical. Several factors which need to be considered include: 1) the pharmacokinetics of the parent chemical, 2) the target tissue concentrations of the parent chemical or its bioactivated proximate toxicant, 3) the uptake kinetics of the parent chemical or metabolite into the target cell(s) and/or membrane interactions, and 4) the interaction of the chemical or metabolite with presumed receptor site(s). Because these theoretical factors each contain a saturable step due to definitive amounts of required enzyme, reuptake or receptor site(s), a nonlinear, saturable dose-response curve would be predicted. In order to exemplify this process, effects of the neurotoxicant, methlenedioxymethamphetamine (MDMA), were reviewed and analyzed. Our results and those of others indicate that: 1) peak concentrations of MDMA and metabolites are ochieved in rat brain by 30 min and are negligible by 24 hr, 2) a metabolite of MDMA is probably responsible for its neurotoxic effects, and 3) pretreatment with monoamine uptake blockers prevents MDMA neurotoxicity. When data generated from rats administerde MDMA were plotted as bilolgical effect (decreases in hippocampal serotonin concentrations) versus dose, a saturation curve best described the observed relationship. These results support the hypothesis that at least one saturable step is involved in MDMA neurotoxicity. We conclude that the mathematical relationship between biological effect and dose of MDMA, the first step of our quantitative neurotoxicity risk assessment procedure, should reflect this biological model information generated from the whole of the dose-response curve.

• Radiation Oncology Journal
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• v.38 no.1
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• pp.35-43
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• 2020

Purpose: This retrospective study compares higher-dose whole-brain radiotherapy (hdWBRT) with reduced-dose WBRT (rdWBRT) in terms of clinical efficacy and toxicity profile in patients treated for primary central nervous system lymphoma (PCNSL). Materials and Methods: Radiotherapy followed by high-dose methotrexate (HD-MTX)-based chemotherapy was administered to immunocompetent patients with histologically confirmed PCNSL between 2000 and 2016. Response to chemotherapy was taken into account when prescribing the radiation dose to the whole brain and primary tumor bed. The whole brain dose was ≤23.4 Gy for rdWBRT (n = 20) and >23.4 Gy for hdWBRT (n = 68). Patients manifesting cognitive disturbance, memory impairment and dysarthria were considered to have neurotoxicity. A median follow-up was 3.62 years. Results: The 3-year overall survival (OS) and progression-free survival (PFS) were 70.0% and 48.9% with rdWBRT, and 63.2% and 43.2% with hdWBRT. The 3-year OS and PFS among patients with partial response (n = 45) after chemotherapy were 77.8% and 53.3% with rdWBRT, and 58.3% and 45.8% with hdWBRT (p > 0.05). Among patients with complete response achieved during follow-up, the 3-year freedom from neurotoxicity (FFNT) rate was 94.1% with rdWBRT and 62.4% with hdWBRT. Among patients aged ≥60 years, the 3-year FFNT rate was 87.5% with rdWBRT and 39.1% with hdWBRT (p = 0.49). Neurotoxicity was not observed after rdWBRT in patients aged below 60 years. Conclusion: rdWBRT with tumor bed boost combined with upfront HD-MTX is less neurotoxic and results in effective survival as higher-dose radiotherapy even in partial response after chemotherapy.