• The Korean Journal of Physiology and Pharmacology
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• 제20권3호
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• pp.279-286
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• 2016

Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging effect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral deficits on the rotarod test were significantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant effect and can be used as a potential therapeutic agent against HD.

• The Korean Journal of Physiology and Pharmacology
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• 제20권2호
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• pp.185-192
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• 2016

Ampicillin, a ${\beta}$-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G significantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus.

• The Korean Journal of Physiology and Pharmacology
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• 제21권1호
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• pp.125-131
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• 2017

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

• Animal cells and systems
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• 제9권2호
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• pp.101-105
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• 2005

[ ${\beta}ig-h3$ ] is a secretory protein that is induced by $TGF-{\beta}$ and implicated in various disease conditions including fibrosis. We have previously reported that ${\beta}ig-h3$ expression is implicated in astrocyte response to brain injury. In this study, we further investigated potential roles of ${\beta}ig-h3$ protein in the injured central nervous system (CNS). We specifically assessed whether the treatment of microglial cells with ${\beta}ig-h3$ can regulate microglial activity. Microglial cells are the prime effector cells in CNS immune and inflammatory responses. When activated, they produce a number of inflammatory mediators, which can promote neuronal injury. We prepared conditioned medium from the stable CHO cell line transfected with human ${\beta}ig-h3$ cDNA. We then examined the effects of the conditioned medium on the LPS- or $IFN-{\gamma}-mediated$ induction of proinflammatory molecules in microglial cells. Preincubation with the conditioned medium significantly attenuated LPS-mediated upregulation of $TNF-{\alpha},\;IL-1{\beta}$, iNOS and COX-2 mRNA expression in BV2 murine microglial cells. It also reduced $IFN-{\gamma}-mediated$ upregulation of $TNF-{\alpha}$ and COX-2 mRNA expression but not iNOS mRNA expression. Assays of nitric oxide release correlated with the mRNA data, which showed selective inhibition of LPS-mediated nitric oxide production. Although the regulatory mechanisms need to be further investigated, these results suggest that astrocyte-derived ${\beta}ig-h3$ may contribute to protection of the CNS from immune-mediated damage via controlling microglial inflammatory responses.

• Korean Journal of Medicinal Crop Science
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• 제15권2호
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• pp.105-111
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• 2007

The protective effect of ethanol extract of Korean mistletoe (KM; Viscum album coloratum) on hydrogen peroxide $(H_{2}O_{2})-induced$ neurotoxicity was examined in primary cultured rat cortical neurons. $H_{2}O_{2}$ reduced viability of cortical neurons in a concentration-dependent manner. The addition of KM, over a concentration range of 10 to 100 ${\mu}g/ml$, concentration-dependently prevented the $H_{2}O_{2}(100\;{\mu}M)-induced$ neuronal cell death, as assessed by a 3-[4,5-dimethylthiazol-2-yl]-2,5-di-phenyl-tetrazolium bromide (MTT) assay and Hoechst 33342 staining. KM significantly inhibited $H_{2}O_{2}-induced$ elevation of the cytosolic $Ca^{2+}$ concentration $([Ca^{2+}]_{c})$, which was measured by a fluorescent dye, fluo-4 AM. KM inhibited glutamate release into medium and generation of reactive oxygen species (ROS) induced by $H_{2}O_{2}$. These results suggest that KM may mitigate the $H_{2}O_{2}-induced$ neurotoxiciy by interfering with the increase of $[Ca^{2+}]_{c}$, and inhibiting glutamate release and generation of ROS in cultured neurons.

• Korean Journal of Biological Psychiatry
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• 제24권1호
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• pp.1-9
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• 2017

The proton magnetic resonance spectroscopy ($^1H-MRS$) is a tool used to detect concentrations of brain metabolites such as N-acetyl aspartate, choline, creatine, glutamate, and gamma-amino butyric acid (GABA). It has been widely used because it does not require additional devices other than the conventional magnetic resonance scanner and coils. Demyelination, or the neuronal damage due to loss of myelin sheath, is one of the common pathologic processes in many diseases including multiple sclerosis, leukodystrophy, encephalomyelitis, and other forms of autoimmune diseases. Rodent models mimicking human demyelinating diseases have been induced by using virus (e.g., Theiler's murine encephalomyelitis virus) or toxins (e.g., cuprizon or lysophosphatidyl choline). This review is an overview of the MRS findings on brain metabolites in demyelination with a specific focus on rodent models.

• Proceedings of the KSMRM Conference
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• 대한자기공명의과학회 2001년도 제6차 학술대회 초록집
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• pp.172-172
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• 2001

Purpose： To evaluate compensatory change of opposite hippocampus after temporal lobe surgery in th patient with temporal lobe epilepsy by using single-voxel proton MR spectroscopy. Method： Eighteen patients with intractable temporal lobe epilepsy (TLE) whose MR diagnos was unilateral hippocampal sclerosis (n=11) or localized unilateral anterior temporal lobe lesio (n=7) and who underwent anterior temporal lobectomy were included in the study. Singl proton MRS of opposite hippocampus was carried out on the same day or within 1 week af MR imaging before temporal lobe surgery and after over 1-year post-surgical follow-u Single voxel proton MRS were acquired using GE signa 1.5T scanner and spectrosco system (TR, 1500-2, 000： TE, 136-144). Region of interest (ROI) was placed in a simitar position for all examination to cover the medial temporal lobes including most of the head an body of hippocampus and a part of amygdala, the parahippocampal gyrus. The MR spectr were evaluated with a focus on the metabolite ratio of N-acetylaspartate (NAA choline-containing phospholipids (Cho), creatine (Cr). The metabolite ratios of NAA/ Cr were calculated from the relative peak height measurement. We evaluated change of th intensity ratio NAA/Cr between before and after surgery, to simplify quantification acro patients, because observed decreases in the ratio of NAA/Cr can be interpreted in terms o neuronal or axonal damage.

• Journal of Physiology & Pathology in Korean Medicine
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• 제23권5호
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• pp.969-973
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• 2009

Samul-tang (SMT), which was firstly described in (Hwajegukbang) Song dynasty, is well known remedy for blood diseases in Oriental medicine. SMT is traditional herbal-remedy composed of Rehmanniae Radix Preparat, Angelicae Gigantis Radix, Cnidii Rhizoma and Paeoniae Radix. Recently, SMT has known to have anti-oxidative action. However, the reports on anti-oxidantic action in neuroglial cells are rare. In addition, the exact mechanisms are unclear. For these reasons, we investigated the protective effects of SMT on cell death induced by oxidative stress using C6 glioma cells. In our results, SMT accelerated proliferation rates of C6 cells in vitro. In addition, levels of LDH release induced by oxidative stress were lowered by treatment with SMT. Finally, protective effects on cell death induced by chemicals such as paraquat and rotenone were observed. In conclusion, these results suggest the possibility to protect brain cell or neuronal cell from damage induced by oxidative stress.

• Journal of Oriental Neuropsychiatry
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• 제11권1호
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• pp.1-18
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• 2000

To study the effects of Ramulus et Uncus Uncariae (REUU) on oxygen free radical-mediated damage by hydrogen peroxide $(H_{2}O_{2})$ on cultured spinal sensory neurons, in vitro assays such as MTT assay, NR assay, neurofilament enzymeimmuno assay (EIA), sulforhodamine B (SRB) assay, assay for lactate dehydrogenase (LDH) activity and assay for lipid peroxidation were used in cultured spinal dorsal root ganglion neurons derived from mice, Spinal dorsal root ganglion neurons were cultured in media containing various concentrations of $H_{2}O_{2}$ for 5 hours, after which the neurotoxic effect of $H_{2}O_{2}$ was measured by in vitro assay. The protective effect of the herb extract, Ramulus et Uncus Uncariae (REUU) against H2O2-induced neurotoxicity was also examined. The results are as follows. 1. In NR assay and MTT assay, $H_{2}O_{2}$ significantly decreased the cell viability of cultured mouse spinal dorsal root ganglion neurons according to exposure concentration in these cultures. An additional time course study was done on these cultures. 2. Cultured spinal dorsal root ganglion neurons which were exposed to various concentrations of $H_{2}O_{2}$ showed a quantitative decrease of neuronal cells by EIA and of total protein by sulforhodamine B (SRB) assay, while they showed an increase of both lipid peroxidation and LDH activity. 3. The effect of Ramulus et Uncus Uncariae (REUU) on $H_{2}O_{2}$ induced neurotoxicity showed a quantitative increase in both neurofilament and total protein, but showed a decrease of lipid peroxidation and LDH activity. These results suggest that $H_{2}O_{2}$ has a neurotoxic effect on cultured spinal dorsal root ganglion neurons from mice and that the herb extract, Ramulus et Uncus Uncariae (REUU), was very effective in protecting $H_{2}O_{2}$ induced neurotoxicity by decreasing lipid peroxidation and LDH activity.

• The Korean Journal of Physiology and Pharmacology
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• 제18권2호
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• pp.129-134
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• 2014

It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson's disease (PD) and subsequent compensative increase of tetrahydrobiopterin ($BH_4$) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of $BH_4$ into neuron would induce the neuronal toxicity in vitro. To elucidate a role of $BH_4$ in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and $BH_4$ at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and $BH_4$ levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of $BH_4$ was higher than that of DA in early phase. However, the expression level of GTP-cyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of $BH_4$ in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both $BH_4$ and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of $BH_4$ can deteriorate the disease progression in early phase of PD, and the inhibition of $BH_4$ increase could be a strategy for PD treatment.