Seol-Heui Han

Konkuk University, Sŏul, Seoul, South Korea

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Publications (85)173.8 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Resveratrol (3,5,4'-trihydroxy-trans-stilbene, RSV) is a polyphenolic compound present in a variety of plant species (including grapes) that produces a myriad of biological activities including anti-inflammatory, antioxidant and neuroprotective effects. In this study, we investigate the effects of resveratrol on the basal and glutamate-stimulated expression and activity of a tissue plasminogen activator (tPA) that plays neuromodulatory or neurotoxic roles in many different neurological situations. Under basal conditions, resveratrol decreased the tPA expression and activity without affecting the tPA mRNA level in rat primary cortical neurons. RSV induced AMPK phosphorylation and inhibited mTOR phosphorylation. Inhibition of AMPK phosphorylation using compound C prevented resveratrol-induced down-regulation of tPA activity. This suggested that AMPK/mTOR-dependent translational inhibition contributes to the down-regulation of the tPA. Under glutamate-stimulated conditions of rat primary cortical neurons, tPA activity and expression were increased along with increased tPA mRNA expression but afterward treatment of RSV inhibited the glutamate-induced increase in tPA activity and expression and tPA mRNA expression. Glutamate stimulation induced activation of Akt and MAPK pathways as well as mTOR which were inhibited by RSV. Interestingly, the Erk pathway inhibitor U0126, but neither PI3K-Akt inhibitor LY294002 nor p38 inhibitor SB203580, mimicked the inhibitory action of RSV on glutamate-induced tPA up-regulation. This suggested the essential role of Erk in the transcriptional up-regulation of tPA expression, which is targeted by RSV. Glutamate stimulation induced neuronal cell death as determined by PI staining and MTT assay. However, RSV protected the cultured rat primary cortical neurons from glutamate-induced cell death as paralleled with the changes in tPA expression. These results suggested that RSV can modulate tPA activity under basal and stimulated conditions by both translational and transcriptional mechanisms. The regulation of the tPA by RSV provides additional therapeutic targets on top of the growing number of molecular substrates of RSV's action in the brain.
    Food & function. 03/2014;
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    ABSTRACT: Anticipatory dementia is related to anxiety, which is a clinical predictor of early conversion to Alzheimer's disease. The Fear of Alzheimer's Disease Scale (FADS) is a reliable and valid instrument to address anticipatory dementia. The aim of the present investigation was to develop the Korean version of the Fear of Alzheimer's Disease Scale (K-FADS) and to verify its reliability and validity. We developed the K-FADS to consist of 30 items with total scores ranging from 0 to 120, as in the original FADS. One hundred eight healthy volunteer participants, drawn from 3 different university hospitals, were evaluated. The K-FADS revealed good reliability (Cronbach α=0.96) and good validity as compared to the Korean version of the State-Trait Anxiety Inventory Form (r=0.242, P=0.013). Test-retest reliability was excellent, as the intra-class correlation coefficient comparing the retest to test was 0.98 (95% confidence interval, 0.96-0.99). Our results show that the K-FADS is a suitable and valuable scale to assess anticipatory dementia in elderly Koreans.
    Journal of Korean medical science 03/2014; 29(3):411-5. · 0.84 Impact Factor
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    ABSTRACT: Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 02/2014; · 2.97 Impact Factor
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    ABSTRACT: Background: Alzheimer's disease (AD) is a devastating illness that results in progressive cognitive decline and neuropsychiatric symptoms. The neuropsychiatric symptoms are associated with a rapid decline in cognition and activities of daily living and increased mortality, however the neuroanatomical localisation involved in the development of neuropsychiatric symptoms remains poorly understood. The aim of this study was to identify the association with the regional volume of the insular cortex and each neuropsychiatric symptom in patients with AD. Methods: Subjects diagnosed with AD (n = 40) were evaluated. Magnetic resonance images were obtained and the insular cortex was subdivided into four subregions through the central sulcus of the insula and bilaterally: right anterior insular cortex, right posterior insular cortex, left anterior insular cortex and left posterior insular cortex. The neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A partial correlation analysis was performed. Results: A significant negative correlation existed between apathy, the irritability subscale score and the volume ratio of the bilateral anterior insular cortex and right posterior insular cortex (r = -0.457, -0.433 and -0.572, respectively, p = 0.032, 0.044 and 0.005, respectively). Conclusion: The findings suggest that the regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in AD patients. © 2014 S. Karger AG, Basel.
    European Neurology 01/2014; 71(5-6):125-131. · 1.50 Impact Factor
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    ABSTRACT: Aims: Chronic cerebral hypoperfusion (CCH) is a common pathological factor that contributes to neurodegenerative diseases such as vascular dementia (VaD). Although oxidative stress has been implicated strongly in the pathogenesis of VaD, the molecular mechanism underlying the selective vulnerability of hippocampal neurons to oxidative damage remains unknown. We assessed whether the NADPH oxidase (Nox) complex, a specialized superoxide generation system, plays a role in VaD by permanent ligation of bilateral common carotid arteries in rats. Results: Male Wistar rats (10 weeks of age) were subjected to bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Nox1 expression increased gradually in hippocampal neurons, starting 1 week after 2VO and up to 15 weeks after 2VO. The levels of superoxide, DNA oxidation, and neuronal death in the CA1 subfield of the hippocampus, as well as consequential cognitive impairment, were increased in 2VO rats. Both inhibitions of Nox by apocynin, a putative Nox inhibitor, and adeno-associated virus-mediated Nox1 knockdown reduced significantly 2VO-induced ROS generation, oxidative DNA damage, hippocampal neuronal degeneration, and cognitive impairment. Innovation and Conclusion: We provided evidence that neuronal Nox1 is activated in the hippocampus under CCH, causing oxidative stress and consequential hippocampal neuronal death and cognitive impairment. This evidence implies that Nox1-mediated oxidative stress plays an important role in neuronal cell death and cognitive dysfunction in VaD. Nox1 may serve as a potential therapeutic target for VaD.
    Antioxidants & Redox Signaling 12/2013; · 8.20 Impact Factor
  • Yeonsil Moon, Heejin Kim, Seol-Heui Han
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    ABSTRACT: Abstract Introduction: The purpose of this study is to determine whether vascular risk factors are associated with severity of neuropsychiatric symptoms in patients of Alzheimer's dementia. Methods: We reviewed medical records of 162 patients with Alzheimer's dementia. The NPS were assessed using the Neuropsychiatric Inventory. Hypertension and cardiovascular events were detected through detailed history taking. Diabetes mellitus and hyperlipidemia were uncovered through laboratory test. The asymptomatic stroke and white matter hyperintensities were defined by magnetic resonance imaging. Partial correlation analysis was used. Results: Hypertension was correlated with the severity of apathy (r = 0.231, p = 0.015). The asymptomatic stroke was related to the severity of depression (r = 0.255, p = 0.007). The remaining vascular factors were not significant. Conclusion: Presence of hypertension and asymptomatic stroke are related with the severity of apathy and depression in Alzheimer's dementia.
    The International journal of neuroscience 11/2013; · 0.86 Impact Factor
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    ABSTRACT: Korean Red Ginseng (KRG) is an oriental herbal preparation obtained from Panax ginseng Meyer (Araliaceae). To expand our understanding of the action of KRG on central nervous system (CNS) function, we examined the effects of KRG on tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) expression in rat primary astrocytes. KRG extract was treated in cultured rat primary astrocytes and neuron in a concentration range of 0.1 to 1.0 mg/mL and the expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and reverse transcription-polymerase chain reaction. KRG extracts increased PAI-1 expression in rat primary astrocytes in a concentration dependent manner (0.1 to 1.0 mg/mL) without affecting the expression of tPA itself. Treatment of 1.0 mg/mL KRG increased PAI-1 protein expression in rat primary astrocytes to 319.3±65.9% as compared with control. The increased PAI-1 expression mediated the overall decrease in tPA activity in rat primary astrocytes. Due to the lack of PAI-1 expression in neuron, KRG did not affect tPA activity in neuron. KRG treatment induced a concentration dependent activation of PI3K, p38, ERK1/2, and JNK in rat primary astrocytes and treatment of PI3K or MAPK inhibitors such as LY294002, U0126, SB203580, and SP600125 (10 μM each), significantly inhibited 1.0 mg/mL KRG-induced expression of PAI- 1 and down-regulation of tPA activity in rat primary astrocytes. Furthermore, compound K but not other ginsenosides such as Rb1 and Rg1 induced PAI-1 expression. KRG-induced up-regulation of PAI-1 in astrocytes may play important role in the regulation of overall tPA activity in brain, which might underlie some of the beneficial effects of KRG on CNS such as neuroprotection in ischemia and brain damaging condition as well as prevention or recovery from addiction.
    Journal of ginseng research 10/2013; 37(4):401-12. · 2.26 Impact Factor
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    ABSTRACT: Despite the important role of tissue plasminogen activator (tPA) as a neuromodulator in neurons, microglia, and astrocytes, its role in neural progenitor cell (NPC) development is not clear yet. We identified that tPA is highly expressed in NPCs compared with neurons. Inhibition of tPA activity or expression using tPA stop, PAI-1, or tPA siRNA inhibited neurite outgrowth from NPCs, while overexpression or addition of exogenous tPA increased neurite outgrowth. The expression of Wnt and β-catenin as well as phosphorylation of LRP5 and LRP6, which has been implicated in Wnt-β-catenin signaling, was rapidly increased after tPA treatment and was decreased by tPA siRNA transfection. Knockdown of β-catenin or LRP5/6 expression by siRNA prevented tPA-induced neurite extension. NPCs obtained from tPA KO mice showed impaired neurite outgrowth compared with WT NPCs. In ischemic rat brains, axon density was higher in the brains transplanted with WT NPCs than in those with tPA KO NPCs, suggesting increased axonal sprouting by NPC-derived tPA. tPA-mediated regulation of neuronal maturation in NPCs may play an important role during development and in regenerative conditions.
    Molecular Neurobiology 08/2013; · 5.47 Impact Factor
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    ABSTRACT: The Clinical Research Center for Dementia of South Korea (CREDOS) group developed a new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities (WMHs). In this study, we aimed to evaluate the validity of the CREDOS ischemia classification system. A total of 352 patients with cognitive impairments were included. Their WMH scores were rated using the CREDOS WMH visual rating scale. These patients were divided into 3 groups according to the CREDOS ischemia classification system. The volume of WMH was also automatically measured. The number of lacunes and microbleeds (MBs) were counted. The CREDOS ischemia classification system was revised with factor analysis using vascular risk factors and cerebrovascular disease (CVD) markers (WMH volume, lacunes, and MBs). External validation was performed in another group of patients with cognitive impairment using multinomial logistic regression analysis. The CREDOS WMH visual rating scale showed excellent correlation with the automatically measured volume of WMH. The factor analysis showed that the severe group was expanded to D3P1 and D3P2 in the revised CREDOS ischemia classification system. In the validation group, the presence of vascular risk factors and the severity of CVD markers could be distinguished according to the revised CREDOS ischemia classification. We validated a newly developed classification system for ischemia. This simple visual classification system was capable of providing information on vascular risk factors and CVD markers by simply rating WMH on magnetic resonance imaging.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 07/2013;
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    ABSTRACT: Cytoplasmic polyadenylation binding protein 1 (CPEB1) is a RNA binding protein, which regulates translation of target mRNAs by regulating polyadenylation status. CPEB1 plays important roles in the regulation of germline cell development by modulating cell cycle progression through the polyadenylation of target mRNAs such as cyclin B1. Similar mechanism is reported in proliferating astrocytes by us, although CPEB1 is involved in the transport of target mRNAs as well as local translation at dendritic spines. In this study, we found the expression of CPEB1 in cultured rat primary neural progenitor cells (NPCs). EGF stimulation of cultured NPCs induced rapid phosphorylation of CPEB1, a hallmark of CPEB1-dependent translational control along with cyclin B1 polyadenylation and translation. EGF-induced activation of ERK1/2 and Aurora A kinase was responsible for CPEB1 phosphorylation. Pharmacological inhibition studies suggested that ERK1/2 is involved in the activation of Aurora A kinase and regulation of CPEB1 phosphorylation in cultured NPCs. Long-term incubation in EGF resulted in the down-regulation of CPEB1 expression, which further increased expression of cyclin B1 and cell cycle progression. When we down-regulated the expression of CPEB1 in NPCs by siRNA transfection, the proliferation of NPCs was increased. Increased NPCs proliferation by down-regulation of CPEB1 resulted in eventual up-regulation of neuronal differentiation with increase in both pre- and post-synaptic proteins. The results from the present study may suggest the importance of translational control in the regulation of neuronal development, an emerging concept in many neurodevelopmental and psychiatric disorders such as autism spectrum disorder.
    Neurochemical Research 07/2013; · 2.13 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors (HDACi)-valproic acid (VPA) and trichostatin A (TSA) promote neurogenesis, neurite outgrowth, synaptic plasticity and neuroprotection. In this study, we investigated whether VPA and TSA promote post-ischemic neuroprotection and neuronal restoration in rat primary cortical neurons. On 6 days in vitro (DIV), cortical neurons were exposed to oxygen-glucose deprivation for 90 min. Cells were returned to normoxic conditions and cultured for 1, 3, or 7 days with or without VPA and TSA. Control cells were cultured in normoxic conditions only. On 7, 9, and 13 DIV, cells were measured neurite outgrowth using the Axiovision program and stained with Tunel staining kit. Microtubule associated protein-2 immunostaining and tunel staining showed significant recovery of neurite outgrowth and post-ischemic neuronal death by VPA or TSA treatment. We also determined levels of acetylated histone H3, PSD95, GAP 43 and synaptophysin. Significant increases in all three synaptic markers and acetylated histone H3 were observed relative to non-treated cells. Post-ischemic HDACi treatment also significantly raised levels of brain derived neurotrophic factor (BDNF) expression and secreted BDNF. Enhanced BDNF expression by HDACi treatment might have been involved in the post-ischemic neuroprotection and neuronal restorative effects. Our findings suggest that both VPA and TSA treatment during reoxygenation after ischemia may help post-ischemic neuroprotection and neuronal regeneration via increased BDNF expression and activation.
    Neurochemical Research 06/2013; · 2.13 Impact Factor
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    ABSTRACT: The recruitment of neutrophils into the cerebral microcirculation occurs, especially, in acute brain diseases like a focal cerebral ischemia and plays important role in pathological processes. Proteinases 3 is one of the three major proteinases expressed in neutrophils but no reports are available whether proteinase 3 can modulate neuronal survival. In this study, treatment of cultured rat primary cortical neuron with proteinase 3 induced overt reactive oxygen species production and decreased total glutathione contents as well as disruption of mitochondrial transmembrane potential. Proteinase 3 induced neuronal cell death as evidenced by MTT analysis as well as propidium iodide staining, which was prevented by pretreatment with an antioxidant, N-acetyl cysteine. Proteinase 3 increased activation of procaspase-3 and altered expression level of apoptotic regulator proteins, such as Bcl-2, Bax, and Bcl-xL. Similar to in vitro data, a direct microinjection of proteinase 3 into striatum of rat brain induced neuronal death, which was mediated by reactive oxygen species. These results suggest that proteinase 3 is new essential regulator of neuronal cell death pathway in a condition of excess neutrophil encounter in neuroinflammatory conditions.
    Neuroscience Letters 06/2013; · 2.03 Impact Factor
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    ABSTRACT: Background:Extrapyramidal signs (EPSs) are commonly observed in patients with Alzheimer disease (AD). We report here the base rate of EPS in a large cohort of patients with AD who were not receiving neuroleptic drugs, and the associations of EPS with functional outcomes and depressive symptoms.Methods:In a consortium involving 56 clinics, we recruited 2614 patients with AD. We estimated basic activities of daily living (ADL) and instrumental ADL by the Barthel index and the Seoul-Instrumental Activities of Daily Living (S-IADL) scales, respectively. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). The EPS group was defined by the presence of at least 1 EPS based on a focused neurologic examination.Results:The prevalence of EPS-positive patients was 12%. These had lower Korean version of the Mini-Mental State Examination (K-MMSE) scores than the EPS-negative cases (P < .001). After controlling for demographic, medical, radiological, genetic, and cognitive (K-MMSE) factors, the proportion of patients with impaired ADL was significantly higher in the EPS group than in the non-EPS group (P < .001, odds ratio = 1.90, 95% confidence interval, 1.45-2.48, and logistic regression). The S-IADL scores were significantly higher in the EPS group than this in the non-EPS group (P < .001, regression coefficient = 3.19, and median regression). The GDS-15 scores were higher in the EPS group (P = .04, regression coefficient = 0.89, and median regression).Conclusion:The presence of EPS in patients with AD who were not receiving neuroleptic drugs was associated with more impaired basic and instrumental ADL functioning and with greater depression symptoms.
    Journal of Geriatric Psychiatry and Neurology 06/2013; · 3.53 Impact Factor
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    ABSTRACT: Although the role of α-synuclein aggregation on Parkinson's disease is relatively well known, the physiological role and the regulatory mechanism governing the expression of α-synuclein are unclear yet. We recently reported that α-synuclein is expressed and secreted from cultured astrocytes. In this study, we investigated the effect of valproic acid (VPA), which has been suggested to provide neuroprotection by increasing α-synuclein in neuron, on α-synuclein expression in rat primary astrocytes. VPA concentrationdependently increased the protein expression level of α-synuclein in cultured rat primary astrocytes with concomitant increase in mRNA expression level. Likewise, the level of secreted α-synuclein was also increased by VPA. VPA increased the phosphorylation of Erk1/2 and JNK and pretreatment of a JNK inhibitor SP600125 prevented the VPA-induced increase in α-synuclein. Whether the increased α-synuclein in astrocytes is involved in the reported neuroprotective effects of VPA awaits further investigation.
    Biomolecules and Therapeutics 05/2013; 21(3):222-228. · 0.79 Impact Factor
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    ABSTRACT: The peroxisome proliferator-activated receptor gamma (PPARγ) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the molecular mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau-Thr(231) phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymatic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr(231) phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the observed inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARγ antagonist, did not alter the observed inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr(231) phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3β, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same observed inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr(231) phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degradation of p35 and a PPARγ-independent signaling pathway. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 04/2013; · 3.97 Impact Factor
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    ABSTRACT: AIMS: Tissue plasminogen activator (tPA) is an essential neuromodulator whose involvement in multiple functions such as synaptic plasticity, cytokine-like immune function and regulation of cell survival mandates rapid and tight tPA regulation in the brain. We investigated the possibility that a transient metabolic challenge induced by glucose deprivation may affect tPA activity in rat primary astrocytes, the main cell type responsible for metabolic regulation in the CNS. MAIN METHODS: Rat primary astrocytes were incubated in serum-free DMEM without glucose. Casein zymography was used to determine tPA activity, and tPA mRNA was measured by RT-PCR. The signaling pathways regulating tPA activity were identified by Western blotting. KEY FINDINGS: Glucose deprivation rapidly down-regulated the activity of tPA without affecting its mRNA level in rat primary astrocytes; this effect was mimicked by translational inhibitors. The down-regulation of tPA was accompanied by increased tPA degradation, which may be modulated by a proteasome-dependent degradation pathway. Glucose deprivation induced activation of PI3K-Akt-GSK3β, p38 and AMPK, and inhibition of these pathways using LY294002, SB203580 and compound C significantly inhibited glucose deprivation-induced tPA down-regulation, demonstrating the essential role of these pathways in tPA regulation in glucose-deprived astrocytes. SIGNIFICANCE: Rapid and reversible regulation of tPA activity in rat primary astrocytes during metabolic crisis may minimize energy-requiring neurologic processes in stressed situations. This effect may thereby increase the opportunity to invest cellular resources in cell survival and may allow rapid re-establishment of normal cellular function after the crisis.
    Life sciences 04/2013; · 2.56 Impact Factor
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    ABSTRACT: The Literacy-Independent Cognitive Assessment (LICA) has been developed for a diagnosis of dementia and is a useful neuropsychological test battery for illiterate populations as well as literate populations. The objective of this study was to develop the short form of the LICA (S-LICA) and to evaluate the reliability and validity of the S-LICA. The subtests of the S-LICA were selected based on the factor analysis and validation study results of the LICA. Patients with dementia (n=101) and normal elderly controls (n=185) participated in this study. Cronbach's coefficient alpha of the S-LICA was 0.92 for illiterate subjects and 0.94 for literate subjects, and the item-total correlation ranged from 0.63 to 0.81 (p<.01).The test-retest reliability of the S-LICA total score was high (r=0.94, p<.001), and the subtests had high test-retest reliabilities (r=0.68-0.87, p<.01). The correlation between the K-MMSE and S-LICA total scores were substantial in both the illiterate subjects (r=0.837, p<.001) and the literate subjects(r=0.802, p<.001). The correlation between the S-LICA and LICA was very high (r=0.989, p<.001). The area under the curve of the receiver operating characteristic was 0.999 for the literate subjects and 0.985 for the illiterate subjects. The sensitivity and specificity of the S-LICA for a diagnosis of dementia were 97% and 96% at the cutoff point of 72 for the literate subjects, and 96% and 93% at the cutoff point of 68 for the illiterate subjects, respectively. Our results indicate that the S-LICA is a reliable and valid instrument for quick evaluation of patients with dementia in both illiterate and literate elderly populations.
    Journal of Clinical Neurology 04/2013; 9(2):111-7. · 1.89 Impact Factor
  • Hee-Jin Kim, Won-Jin Moon, Seol-Heui Han
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    ABSTRACT: BACKGROUND: This study aimed to evaluate the relationship between loss of white matter cholinergic pathways, atrophy of the nucleus basalis of Meynert (NBM), and cognitive function in patients with subcortical ischemic vascular dementia (SIVD) or Alzheimer's disease (AD). METHODS: The participants included 26 SIVD, 17 probable AD with or without white-matter changes, and 20 age-matched healthy controls. Thin-section coronal T2-weighted images were acquired using 3.0 T MR. The extent of white matter hyperintensities within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). NBM atrophy was assessed from the thickness of the substantia innominata (SI) at the level of the crossing of the anterior commissure. Cognitive impairment was measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Correlations between CHIPSs, SI thickness, and cognitive impairment were evaluated using the Spearman ranked correlation test. RESULTS: In AD, MMSE scores and CDR were correlated with SI thickness (ρ = 0.450, p = 0.006 and ρ = -0.520, p = 0.030, respectively) but not with CHIPS scores (ρ = -0.160, p = 0.530 and ρ = 0.270, p = 0.292, respectively). By contrast, aggravated MMSE score and CDR in SIVD had a tendency to correlate with elevated CHIPS scores (ρ = -0.344, p = 0.127 and ρ = 0.521, p = 0.021, respectively) but not with SI thickness (ρ = -0.210, p = 0.480 and ρ = 0.080, p = 0.736, respectively). CONCLUSIONS: Loss of cholinergic pathways correlates with cognitive dysfunction in both AD and SIVD. The mechanisms appear to differ: NBM atrophy is likely to be the predominant contributor to cognitive impairments in AD, whereas, the cognitive dysfunction of SIVD was associated with compromised subcortical cholinergic fibers not with nucleus itself.
    Journal of Alzheimer's disease: JAD 01/2013; · 4.17 Impact Factor
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    ABSTRACT: Autism spectrum disorder (ASD) is a pervasive developmental disorder characterized by three main behavioral symptoms including social deficits, impaired communication, and stereotyped and repetitive behaviors. ASD prevalence shows gender bias to male. Prenatal exposure to valproic acid (VPA), a drug used in epilepsy and bipolar disorder, induces autistic symptoms in both human and rodents. As we reported previously, prenatally VPA-exposed animals at E12 showed impairment in social behavior without any overt reproductive toxicity. Social interactions were not significantly different between in male and female rats in control condition. However, VPA-exposed male offspring showed significantly impaired social interaction while female offspring showed only marginal deficits in social interaction. Similar male inclination was observed in hyperactivity behavior induced by VPA. In addition to the ASD-like behavioral phenotype, prenatally VPA-exposed rat offspring shows crooked tail phenotype, which was not different between male and female groups. Both male and female rat showed reduced GABAergic neuronal marker GAD and increased glutamatergic neuronal marker vGluT1 expression. Interestingly, despite of the similar increased expression of vGluT1, postsynaptic marker proteins such as PSD-95 and α-CAMKII expression was significantly elevated only in male offspring. Electron microscopy showed increased number of postsynapse in male but not in female at 4weeks of age. These results might suggest that the altered glutamatergic neuronal differentiation leads to deranged postsynaptic maturation only in male offspring prenatally exposed to VPA. Consistent with the increased postsynaptic compartment, VPA-exposed male rats showed higher sensitivity to electric shock than VPA-exposed female rats. These results suggest that prenatally VPA-exposed rats show the male preponderance of ASD-like behaviors including defective social interaction similar to human autistic patients, which might be caused by ectopic increase in glutamatergic synapses in male rats. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12147.
    Journal of Neurochemistry 01/2013; · 3.97 Impact Factor
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    ABSTRACT: During hemorrhagic stroke induced by intracerebral hemorrhage (ICH), brain injury occurs from the deleterious actions of hemoglobin byproducts; induction of heme oxygenase-1 (HO-1) also plays a critical role in the neurotoxicity in ICH. Valproic acid (VPA), which is a commonly used drug in the treatment of epilepsy, has been reported to have neuroprotective effects against various neuronal insults including ischemic stroke. We investigated the effect of VPA on HO-1-mediated neurotoxicity in an experimental model of ICH. We investigated the effects of VPA on HO-1 protein in primary cortical neurons: 1) the expression levels of HO-1 mRNA and protein measured by RT-PCR and Western blotting; 2) the cell viability and ROS generation by MTT reduction assay and ROS measurement; 3) the signal pathway regulated by VPA using IP-Western blotting; 4) the effects of VPA on hemin-induced cell death by hemin microinjection and immunohistochemistry in vivo. VPA treatment partially blocked cell death induced by hemin, which is released from hemoglobin during ICH, both in rat primary cortical neurons and rat brain. Treatment of VPA significantly decreased the expression of HO-1 protein both in vitro and in vivo. Hemin treatment induced HO-1 protein expression and this was partially blocked by pretreatment with VPA, which might be mediated by increased ubiquitination and degradation of HO-1 via ERK1/2 and JNK activation in primary cortical neurons. Our results indicate that VPA inhibits hemin toxicity by downregulating HO-1 protein expression, and provide a therapeutic strategy to attenuate intracerebral hemorrhagic injury.
    Neurochemistry International 01/2013; · 2.66 Impact Factor

Publication Stats

252 Citations
117 Downloads
173.80 Total Impact Points

Institutions

  • 2006–2014
    • Konkuk University
      • • Neuroscience Center
      • • Division of Biological Sciences
      • • Department of Neurology
      Sŏul, Seoul, South Korea
  • 2012–2013
    • Hanyang University
      • College of Medicine
      Ansan, Gyeonggi, South Korea
    • Korea Institute of Oriental Medicine
      Bucheon, Gyeonggi Province, South Korea
    • Sungkyunkwan University
      • Department of Neurology
      Seoul, Seoul, South Korea
  • 2006–2013
    • Konkuk University Medical Center
      • Department of Neurology
      Changnyeong, South Gyeongsang, South Korea
  • 2009–2012
    • Seoul National University
      • • College of Pharmacy
      • • Research Institute of Pharmaceutical Sciences
      Seoul, Seoul, South Korea
  • 2008
    • Inje University
      Kŭmhae, South Gyeongsang, South Korea
  • 2004
    • Inha University
      • Department of Neurology
      Seoul, Seoul, South Korea
    • Chungbuk National University
      • Department of Neurology
      Tyundyu, North Chungcheong, South Korea