• Journal of Ginseng Research
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• 제46권4호
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• pp.572-584
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• 2022

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of trinucleotide CAG repeat in the Huntingtin (Htt) gene. The major pathogenic pathways underlying HD involve the impairment of cellular energy homeostasis and DNA damage in the brain. The protein kinase ataxia-telangiectasia mutated (ATM) is an important regulator of the DNA damage response. ATM is involved in the phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK plays a critical role in response to DNA damage. Herein, we demonstrated that expression of polyQ-expanded mutant Htt (mHtt) enhanced the phosphorylation of ATM. Ginsenoside is the main and most effective component of Panax ginseng. However, the protective effect of a ginsenoside (compound K, CK) in HD remains unclear and warrants further investigation. Methods: This study used the R6/2 transgenic mouse model of HD and performed behavioral tests, survival rate, histological analyses, and immunoblot assays. Results: The systematic administration of CK into R6/2 mice suppressed the activation of ATM/AMPK and reduced neuronal toxicity and mHTT aggregation. Most importantly, CK increased neuronal density and lifespan and improved motor dysfunction in R6/2 mice. Conversely, CK enhanced the expression of Bcl2 protected striatal cells from the toxicity induced by the overactivation of mHtt and AMPK. Conclusions: Thus, the oral administration of CK reduced the disease progression and markedly enhanced lifespan in the transgenic mouse model (R6/2) of HD.

• 대한본초학회지
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• 제28권5호
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• pp.21-28
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• 2013

Objectives : The aim of this study was to investigate the neuroprotective effects and mechanisms of Cyperi Rhizoma extracts (CRE) using in vitro and in vivo models of Parkinson's disease (PD). Methods : We evaluated the neuroprotective effect of CRE against 1-methyl-4-phenylpyridinium (MPP+) toxicity using tyrosine hydroxylase immunohistochemistry (IHC) in primary rat mesencephalic dopaminergic neurons. In addition, the effect of CRE was evaluated in mice PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). For evaluations, C57bl/6 mice were orally treated with CRE 50 mg/kg for 5 days and were injected intraperitoneally with MPTP (20 mg/kg) at 2 h intervals on the last day. To identify the CRE affects on MPTP-induced neuronal loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and striatum of mice, the behavioral tests and IHC analysis were carried out. Also, we conducted nitric oxide (NO) and tumor necrosis factor-alpha (TNF-${\alpha}$) assay in dopaminergic neurons and IHC using glial markers in SNpc of mice to assess the anti-inflammation effects. Results : In primary mesencephalic culture system, CRE protected dopaminergic cells against $10{\mu}M$ MPP+-induced toxicity at 0.2 and $1.0{\mu}g/mL$. In the behavior tests, CRE treated group showed improved motor deteriorations than those in the MPTP only treated group. CRE significantly protected striatal dopaminergic damage from MPTP-induced neurotoxicity in mice. Moreover, CRE inhibited productions of NO and TNF-${\alpha}$ in dopaminergic culture system and activation of astrocyte and microglia in SNpc of the mice. Conclusion : We concluded that CRE shows anti-parkinsonian effect by protecting dopaminergic neurons against MPP+/MPTP toxicities through anti-inflammatory actions.

• 대한환경공학회지
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• 제38권7호
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• pp.395-401
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• 2016

최근 나노물질의 산업 및 생활분야의 광범위한 사용으로 인한 나노안전성이 대두되고 있다. 특히 다양한 목적에 의해 가공된 나노물질의 잠재적 독성이 문제가 되고 있기 때문에, 지속가능한 나노물질 산업의 발전을 위해서는 적극적인 나노 안전성에 대한 연구가 진행되어야 한다. 현재까지 나노물질의 일반적 급성, 만성독성에 대한 연구는 비교적 활발하게 진행되고 있지만, 나노물질의 다세대 영향에 대한 연구는 시간적 및 실험적 제약으로 인해 미흡한 실정이다. 생태계 내 나노물질의 다세대 연구는 일반적 독성 종말점을 이용한 후세대 영향 연구와 나노물질의 세대 간 거동을 확인한 세대전이 연구로 나뉘어 진행되고 있다. 본 연구는 나노물질의 다세대 영향 및 전이연구 추세를 확인하고 제한점을 제시하여 앞으로의 연구방향을 제시하는데 그 목적이 있다. 나노물질에 대한 학술연구를 대상으로 문헌조사를 실시하였으며, 각 분야별 자료를 수집하고 비교분석하였다. 조사결과 후세대 영향을 확인한 연구는 총 13건 이었으며, 생존률, 생식률 그리고 운동성과 같은 지표를 이용하여 다음세대에 전달되는 영향을 확인하였다. 그리고, 7건의 세대전이 연구에서는 후세대로 전달된 나노물질을 다양한 이미징 기법을 통하여 확인하였다. 현재까지 나노물질이 후세대에 미치는 독성영향의 메커니즘은 밝혀진 바가 거의 없다. 본 연구에서는 나노물질의 다세대 연구추세를 분석하고, 후세대영향과 세대전이의 상호보완적 연구방향을 제시하였다.

• 대한본초학회지
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• 제29권3호
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• pp.27-33
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• 2014

Objectives : The aim of this study was to investigate the protective effect of extract of Thuja orientalis leaves (TOFE) against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity by inhibition of inflammation in in vitro and in vivo models of Parkinson's disease (PD). Methods : We evaluated the effect of TOFE against lipopolysaccharide (LPS)/1-methyl-4-phenylpyridinium ($MPP^+$) toxicity using nitric oxide (NO) assay, inducible NO synthase and cyclooxygenase 2 western blot, tyrosine hydroxylase and microglia activation immunohistochemistry (IHC) in BV2 cell, primary rat mesencephalic neurons, or C57BL/6 mice. We also evaluated the effect of TOFE in mice PD model induced by MPTP. C57BL/6 mice were treated with TOFE 50 mg/kg for 5 days and were injected intraperitoneally with four administrations of MPTP on the last day. We conducted behavioral tests and IHC analysis to see how TOFE affect MPTP-induced neuronal loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and striatum (ST) of mice. To assess the anti-inflammation effects, we carried out glial fibrillary acidic protein and macrophage-1 antigen integrin alpha M in IHC in SNpc and ST of mice. Results : In an in vitro system, TOFE decreasesd NO generations in BV2 cells. TOFE protected dopaminergic cells against LPS or $MPP^+$-induced toxicity in primary mesencephalic dopaminergic neurons. In vivo system, TOFE at 50 mg/kg treated group showed improved motor deteriorations than the MPTP only treated group and TOFE significantly protected striatal dopaminergic damage from MPTP-induced neurotoxicity in mice. Moreover, TOFE inhibited activation of astrocyte and microglia in SNpc and ST of the mice. Conclusions : We concluded that TOFE showed anti-parkinsonian effect by protection of dopaminergic neurons against MPTP toxicity through anti-inflammatory actions.

• International Journal of Stem Cells
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• 제15권3호
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• pp.258-269
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• 2022

Background and Objectives: Currently, safety pharmacological tests for the central nervous system depend on animal behavioral analysis. However, due to the subjectivity of behavioral analysis and differences between species, there is a limit to appropriate nervous system toxicity assessment, therefore a new neurotoxicity assessment that can simulate the human central nervous system is required. Methods and Results: In our study, we developed an in vitro neurotoxicity assessment focusing on neuronal function. To minimize the differences between species and fast screening, hiPSC-derived neurons and a microelectrode array (MEA) that could simultaneously measure the action potentials of the neuronal networks were used. After analyzing the molecular and electrophysiological characters of our neuronal network, we conducted a neurotoxicity assessment on neurotransmitters, neurotoxicants, illicit drugs, and new psychoactive substances (NPS). We found that most substances used in our experiments responded more sensitively to our MEA-based neurotoxicity assessment than to the conventional neurotoxicity assessment. Also, this is the first paper that evaluates various illicit drugs and NPS using MEA-based neurotoxicity assessment using hiPSC-derived neurons. Conclusions: Our study expanded the scope of application of neurotoxicity assessment using hiPSC-derived neurons to NPS, and accumulated evaluation data of various toxic substances for hiPSC-derived neurons.

• 한국약용작물학회지
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• 제27권6호
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• pp.365-375
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• 2019

Background: Oxidative stress plays an important role in neuro-degenerative disorders such as Alzheimer's disease. Oxidative stress is mediated by reactive oxygen species (ROS), which are implicated in the pathogenesis of numerous diseases, and account for the toxicity of a wide range of compounds. Methods and Results: In order to study the neuro-protective effect of the complex extracts of Aster scaber Thunberg (AS) and Chaenoleles sinensis Koehne (CSK) against hydrogen peroxide in PC12 cells, cell viability was evaluated by the MTT assay using tetrazole, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and the intracellular ROS levels were determined the by 2',7'-dichlorofluorescein diacetate (DCF-DA) assay. In order to examine the anti-amnesic effects of the complex extracts of AS and CSK, behavioral tests were performed on male ICR mice. The ameliorating effect of the complex extracts against Aβ_1-42-induced learning and memory impairment was analyzed by y-maze and passive avoidance tests. The AS and CSK extracts showed neuro-protective activity both in vitro and in vivo, and the neuro-protective effect of their 60 : 40 (AS : CSK) mixture was better than that of the other mixtures. Moreover, the complex extracts synergistically inhibited acetylcholinesterase activity and rapid peroxidation. Conclusions: A mixture of the AS and CSK extracts could be used to develop functional foods and serve as raw materials for the development of therapeutics against Alzheimer's disease.

• 동의신경정신과학회지
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• 제28권3호
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• pp.145-156
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• 2017

Objectives: The purpose of this study is to review experimental studies of Parkinson's Disease in Korean medical journals, which have been published since 1990. Methods: Experimental studies related to Parkinson's disease published in Korean medical journals, registered with Korea research foundation, were searched. Articles were grouped into journal of publication, subject, and publication year. Experimental study subjects and models were analysed. Results and Conclusions: Twenty-two articles about experimental studies of Parkinson's Disease in Korean medical journals were included in our review. There were 13 articles in which herbs were used for treatment, 4 articles in which bee venom was used for treatment, 4 articles in which acupuncture was used for treatment, and 1 article in which pharmacopuncture was used for treatment. Most of the studies used experimental models of MPTP-induced Parkinson's disease and MTT assay was used to analyse cell toxicity and cell viability. Pole test, rotarod test, Morris water maze test, and forced swimming test were commonly used to analyse MPTP-induced behavioral deficits in animals. Analysis on experimental studies of Parkinson's disease was categorized into the subjects of dopaminergic cell protective effect, cell-apoptosis protectiveness, anti-inflammatory effect, and anti-oxidative effect.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2005년도 춘계학술대회
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• pp.53-60
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• 2005

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting $1\%$ of the population above the age of 65 and is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although the underlying cause of dopaminergic cell death or the mechanism by which these cells degenerate is still not clearly understood, oxidative stress, mitochondrial dysfunction, and protein misfolding are thought to play important roles in the dopaminergic degeneration in PD. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of the potential oxidative stressors dopamine and nitric oxide. In addition to its contribution toward the syntheses of these two potentially toxic molecules, BH4 itself can directly generate oxidative stress. BH4 undergoes oxidation during the hydroxylation reaction as well as nonenzymatic autooxidation to produce hydrogen peroxide and superoxide radical. We have previously suggested BH4 as an endogenous molecule responsible for the dopaminergic neurodegeneration. BH4 exerts selective toxicity to dopamine-producing cells via generation of oxidative stress, mitochondrial dysfunction, and apoptosis. BH4 also induces morphological, biochemical, and behavioral characteristics associated with PD in vivo. BH4 as well as enzyme activity and gene expression of GTP cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis pathway, are readily upregulated by cellular changes such as calcium influx and by various stimuli including stress situations. This points to the possibility that cellular availability of BH4 might be increased in aberrant conditions, leading to increased extracellular BH4 subsequent degeneration. The fact that BH4 is specifically and endogenously synthesized in dopaminergic cells, Is readily upregulated, and generates oxidative stress-related cell death provides physical relevance of this molecule as an attractive candidate with which to explain the mechanism of pathogenesis of PD.

• Toxicological Research
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• 제31권4호
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• pp.347-354
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• 2015

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout ($Hfe^{-/-}$) and their control wild-type ($Hfe^{+/+}$) mice to $MnCl_2$ in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in $Hfe^{+/+}$ mice, but not in $Hfe^{-/-}$ mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed $Hfe^{+/+}$ compared with water-drinking $Hfe^{+/+}$ mice. However, Mn-exposed $Hfe^{-/-}$ mice spent more time to find the target hole than Mn-drinking $Hfe^{+/+}$ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.

• Toxicological Research
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• 제24권2호
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• pp.137-150
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• 2008

Sexually mature male and female rats were orally intubated with the organophosphorus insecticide, Pestban at a daily dosage of 7.45 or 3.72 mg/kg bwt, equivalent to 1/20 and 1/40 $LD_{50}$, respectively. Male rats were exposed for 70 days, while the female rats were exposed for 14 days, premating, during mating and throughout the whole length of gestation and lactation periods till weaning. The results showed depressed acetylcholinesterase(AChE) activity in the brain of parents, fetuses and their placentae in a dose-dependent manner. The fertility was significantly reduced with increasing the dose in both treated groups, with more pronounced suppressive effects in the male treated group. The number of implantation sites and viable fetuses were significantly reduced in pregnant females of both treated groups. However, the number of resorptions, dead fetuses, and pre-and postimplantation losses were significantly increased. The incidence of resorptions was more pronounced in treated female compared to male group and was dose dependant. The behavioral responses as well as fetal survival and viability indices were altered in both treated groups during the lactation period. The incidence of these effects was more pronounced in the treated female group and occurred in a dose-related manner. The recorded morphological, visceral, and skeletal anomalies were significantly increased with increasing the dose in fetuses of both treated groups, with more pronounced effects on fetuses of treated females. In conclusion, the exposure of adult male and female rats to Pestban would cause adverse effects on fertility and reproduction.