Seol-Heui Han

Konkuk University, Sŏul, Seoul, South Korea

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Publications (128)504.76 Total impact

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    ABSTRACT: Background and purpose: Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Methods: Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Results: Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. Conclusions: White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.
    No preview · Article · Dec 2015 · Stroke
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    ABSTRACT: EGb 761(®) , a standardized extract of Ginkgo biloba leaves, has antioxidant and antiinflammatory properties in experimental models of neurodegenerative disorders such as stroke and Alzheimer's disease. Tissue plasminogen activator (tPA) acts a neuromodulator and plays a crucial role in the manifestation of neurotoxicity leading to exaggerated neuronal cell death in neurological insult conditions. In this study, we investigated the effects of EGb 761 on the basal and glutamate-induced activity and expression of tPA in rat primary cortical neurons. Under basal condition, EGb 761 inhibited both secreted and cellular tPA activities, without altering tPA mRNA level, as modulated by the activation of p38. Compared with basal condition, EGb 761 inhibited the glutamate-induced up-regulation of tPA mRNA resulting in the normalization of overt tPA activity and expression. c-Fos is a component of AP-1, which plays a critical role in the modulation of tPA expression. Interestingly, EGb 761 inhibited c-Fos nuclear translocation without affecting c-Fos expression in glutamate-induced rat primary cortical neurons. These results demonstrated that EGb 761 can modulate tPA activity under basal and glutamate-stimulated conditions by both translational and transcriptional mechanisms. Thus, EGb 761 could be a potential and effective therapeutic strategy in tPA-excessive neurotoxic conditions. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Oct 2015 · Phytotherapy Research
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    ABSTRACT: Proteinase 3 (PR3) is released from neutrophil granules and is involved in the inflammatory process. PR3 is implicated in antimicrobial defense and cell death, but the exact role of PR3 in the brain is less defined. Microglia is the major immune effector cells in the CNS and is activated by brain injury. In the present study, the effect of PR3 on glial activation was investigated. Microglial activation was assessed by the intracellular level of reactive oxygen species and expression of inflammatory cytokines. The conditioned media from activated microglia by PR3 was used for measuring the neurotoxic effects of PR3-stimulated microglia. The effects of PR3 in vivo were measured by microinjecting PR3 into the rat brain. Herein we show that PR3 increased the inflammatory responses including the intracellular ROS and pro-inflammatory cytokine production in rat primary microglia. Conditioned media from PR3-treated microglia induced neuronal cell death in a concentration dependent manner. Furthermore, microinjected PR3 into the striatum of the rat brain induced microglial activation and neuronal cell death. Interestingly treatment with anti-PR3 monoclonal antibody and protease inhibitors ameliorated microglial activation induced by PR3 in primary microglia and striatum, which also prevented neuronal cell death in both conditions. The data presented here suggest that PR3 is a direct modulator of microglial activation and causes neuronal death through the augmentation of inflammatory responses. We suggest that PR3 could be a new modulator of neuroinflammation, and blocking PR3 would be a promising novel therapeutic target for neuroinflammatory disease such as stroke and Alzheimer's disease.
    No preview · Article · Sep 2015 · Neurochemical Research
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    ABSTRACT: In recent years, the average consumption of sugar in humans from all ages has remarkably increased, exceeding the recommended limit. Pregnancy is a critical time for the global development of offsprings who are vulnerable to the deleterious effects of environmental factors. In this study, we investigated whether high sucrose consumption during pregnancy could affect the attention-deficit hyperactivity disorder (ADHD)-like neurobehavioral outcomes in offspring mice. Pregnant mice were randomly grouped and orally administered with either water as control (Con) or 30% wt/vol sucrose diluted in water at 6 (Suc6) or 9 (Suc9) g/kg dosage per day from gestational days 6 to 15. After the weaning period, offspring mice underwent a series of behavioral testing for locomotor activity, attention, and impulsivity. Although there is no obvious difference in gross development of offspring mice such as weight gain, high sucrose-exposed offspring mice showed a significantly increased locomotor activity. Moreover, these mice exhibited a dose-dependent decrease in attention and increase in impulsivity. In the striatum, a significantly increased dopamine transporter (DAT) mRNA expression was found in the Suc9 group along with dose-dependent decreases in the Drd1, Drd2 and Drd4 dopamine receptor subtypes. Furthermore, synaptosomal DAT protein expression was increased about twofold in the Suc9 group. Prenatal fructose exposure also induced hyperactive behavior in offspring mice suggesting the essential role of fructose in the dysregulated neurobehavioral development. These findings suggest prenatal sucrose consumption as a new risk factor for ADHD, which may need further attention and investigation in humans.
    Full-text · Article · Aug 2015 · The Journal of Nutritional Biochemistry
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    ABSTRACT: Comprehensive neuropsychological tests are important in the diagnosis and follow-up of patients with MCI; however, most were developed without consideration of illiteracy. We developed the Literacy Independent Cognitive Assessment (LICA) as a comprehensive neuropsychological assessment battery applicable to older adults who are either literate or illiterate. This study aimed to assess the reliability and validity of the LICA for diagnosis of MCI. Normal controls (n=634) and patients with MCI (n=128) were recruited from 13 centers were included in this study. Participants were divided into illiterate or literate groups, based on their performance on a brief reading and writing test. The LICA, Korean Mini-Mental State Examination (K-MMSE), and Seoul Neuropsychological Screening Battery (SNSB) were administered. Total LICA scores distinguished MCI patients from controls (p<0.001). They were closely and positively correlated to the K-MMSE scores (r=0.632, p<0.001) but negatively correlated to clinical dementia rating (CDR) (r=-0.358, p<0.001) and CDR sum of boxes (r=-0.339, p<0.001). Area under the receiver operating characteristic curve for patients with MCI by total LICA score was 0.827 (0.783-0.870), superior to that presented by the K-MMSE. For the classification of MCI subtypes, inter-method reliability of LICA with the SNSB was good (κ 0.773; 0.679-0.867, p<0.001). The results of this study show that the LICA may be reliably used to distinguish MCI patients from cognitively intact adults, to identify MCI subtypes and monitor progression toward dementia, regardless of illiteracy.
    Full-text · Article · Jul 2015 · Psychiatry investigation
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    ABSTRACT: The aim of this study was to provide normative data on the Literacy Independent Cognitive Assessment (LICA) and to explore the effects of age, education/literacy, and gender on the performance of this test. Eight hundred and eighty-eight healthy elderly subjects, including 164 healthy illiterate subjects, participated in this study. None of the participants had serious medical, psychiatric, or neurological disorders including dementia. Bivariate linear regression analyses were performed to examine the effects of age, education/literacy, and sex on the score in each of the LICA cognitive tests. The normative scores for each age and education/literacy groups are presented. Bivariate linear regression analyses revealed that total score and all cognitive tests of the LICA were significantly influenced by both age and education/literacy. Younger and more-educated subjects outperformed older and illiterate or less-educated subjects, respectively, in all of the tests. The normative scores of LICA total score and subset score were presented according to age (60-64, 65-69, 70-74, 75-80, and ≥80 years) and educational levels (illiterate, and 0-3, 4-6, and ≥7 years of education). These results on demographic variables suggest that age and education should be taken into account when attempting to accurately interpret the results of the LICA cognitive subtests. These normative data will be useful for clinical interpretations of the LICA neuropsychological battery in illiterate and literate elderly Koreans. Similar normative studies and validations of the LICA involving different ethnic groups will help to enhance the dementia diagnosis of illiterate people of different ethnicities.
    Full-text · Article · Jul 2015 · Psychiatry investigation
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    ABSTRACT: Prolonged sleep deprivation is stressful, and could lead to health the consequences such as impairments in vital biological functions of immunity and cognition. Melatonin has significant neuroprotective properties in a number of experimental models. In this study, we investigated the possible role of melatonin can in reversing cognitive dysfunction induced by sleep deprivation in rats. Indeed, our experiments revealed that sleep deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups (P < 0.05). Furthermore, there was increased glial activation most prominent in the hippocampal region of the sleep deprivation (SD) group compared with the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 8-oxo-dG were significantly increased while fragile X-mental retardation protein (FMRP) expression decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following sleep deprivation. Our data suggest that sleep deprivation induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Accordingly, we observed the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in disorders such as Alzheimer's disease and autism. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jun 2015 · Neuroscience
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    ABSTRACT: In the brain, excess zinc promotes the deposition of β-amyloid protein and the intraneuronal accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau protein, which are two key neuropathological traits that reflect Alzheimer’s disease. Egb761, a standardized Ginkgo biloba extract, is a powerful antioxidant that exhibits neuroprotective effects. In this study, we investigated the effects of Egb761 on zinc-induced tau phosphorylation in rat primary cortical neurons. We investigated whether Egb761 administration modified tau phosphorylation in primary cortical neurons by Western blot analyses, MTT assay, ROS measurement and immunocytochemistry. Zinc-induced tau phosphorylation occurred at Ser262 in a time- and dose-dependent manner in rat primary cortical neurons, but other tau sites were not phosphorylated. Tau phosphorylation at Ser262 was increased at 30 min and peaked 3 h after zinc treatment (control: 100 ± 1.2%, 30 min: 253 ± 2.24%, 3 h: 373 ± 1.3%). Egb761 attenuated the zinc-induced tau hyperphosphorylation at Ser262 in a concentration-dependent manner. N-acetylcysteine, an antioxidant, also inhibited the zinc-induced tau phosphorylation at Ser262. Egb761 prevented zinc-induced activation of p38 MAPK and GSK3β. Lithium inhibited the zinc-induced tau phosphorylation. Zinc treatment increased ROS generation and neuronal cell death, and this was effectively prevented by Egb761. These results suggested that Egb761 inhibits zinc-induced tau phosphorylation at Ser262, and this inhibition depends on anti-oxidative actions that occur through the regulation of glycogen synthase kinase 3β. Egb761 may, therefore, be effective in the treatment of tauopathy in neurological disorders, such as Alzheimer’s disease.
    No preview · Article · May 2015
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    Yeonsil Moon · Won-Jin Moon · Hunki Kwon · Jong-Min Lee · Seol-Heui Han
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    ABSTRACT: Background: Emerging evidence suggests that low serum 25-hydroxyvitamin D (25OHD) may induce cognitive decline and dementia, however, the pathophysiological mechanisms are poorly understood. Objective: We sought to determine the relationship between vitamin D deficiency and neuronal integrity in cognitively impaired patients. Methods: One hundred nine patients with memory impairment were divided into quartiles according to serum concentrations of 25OHD concentration, from lowest (L-25OHD) to highest (H-25OHD). The diffusion tensor images from the L-25OHD group and the H-25OHD group were assessed. A mask of regional white matter hyperintensities was obtained in the T1-weighted image space. Data were analyzed using tract-based spatial statistics with a nonlinear registration algorithm. Results: Patients in the L-25OHD group had lower fractional anisotropy values compared with patients in the H-25OHD group in the frontal parts of the inferior and superior longitudinal fasciculi, cingulum bundle, corpus callosum (genu), anterior limb of the internal capsule, and anterior corona radiata (familywise error corrected, p < 0.05). Conclusions: Vitamin D deficiency is associated with disruption of neuronal integrity, primarily in frontal regions. Vitamin D deficiency may lead to the loss of neuroprotective properties in cerebral ischemia and vascular lesions, contributing to memory impairment.
    Full-text · Article · Feb 2015 · Journal of Alzheimer's disease: JAD
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    Yeonsil Moon · Won-Jin Moon · Seol-Heui Han
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    ABSTRACT: The insular cortex is associated with neuropsychiatric symptoms, changes in cardiovascular and autonomic control, and mortality in Alzheimer's dementia. However, the insular cortex does not provide information on the contribution of the other cortices to cognitive decline. We hypothesized that the factors that affect to atrophy in insular cortex are different from other cortical regions. A total of 42 patients with probable Alzheimer's dementia were included in the analyses. The manual drawing of regions of interest was used to detect insular cortex located in the deep gray matter and to avoid coatrophy. Covariates, which could affect to the atrophy of the cerebral cortex, were selected based on previous studies. Any of the demographic factors, vascular risk factors, and the severity scales of dementia was not associated with any insular volume ratio. We suggest that the pathomechanisms of atrophy in insular cortex are different from those of other cortex regions in Alzheimer's disease. © The Author(s) 2015.
    Full-text · Article · Jan 2015 · American Journal of Alzheimer s Disease and Other Dementias
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    ABSTRACT: Background: Cognitive performance changes with chronological aging. Previous studies investigating clinical heterogeneity in frontotemporal dementia (FTD) according to the age of symptom onset did not consider the effect of chronological aging on cognition. Objective: We compared cognitive and behavioral symptoms in patients with early-onset (EO) and late-onset (LO) FTD with consideration of chronological aging effect. Methods: A total of 166 FTD patients were enrolled consecutively from multi-center memory clinics using a nationwide FTD register. To control for the effects of chronological aging on neuropsychological scores, seven hundred and two subjects with normal cognition were also enrolled and regression models were set up. Neuropsychological scores that were detrended with the regression models and the behavioral symptoms of the EO-FTD and LO-FTD groups were compared. Subgroup analyses were performed for three main subtypes of FTD, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA). Results: Among 166 FTD patients, there were 76 bvFTD, 57 SD, and 33 PNFA patients who met new diagnostic criteria for bvFTD or primary progressive aphasia, respectively. LO-FTD (48.2%) was more common than previously thought and the proportions of EO and LO groups differed across FTD subtypes. EO-FTD patients had lower memory and frontal/executive scores and more prominent frontal/behavioral symptoms than LO-FTD patients. Conclusion: Our study suggested that FTD could be heterogeneous with respect the age of symptom onset. After controlling for the effects of chronological aging, EO-FTD patients exhibited more profound memory and frontal/executive dysfunction and more behavioral symptoms than LO-FTD patients.
    Full-text · Article · Jan 2015 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: The positive effects of galantamine on cognition and activities of daily living (ADL) in Alzheimer's disease (AD) are thought to be mediated via improvements in attention. The purpose of this study was to determine the effect of galantamine on attention in AD patients using a computerized attention test and to elucidate the relationship between improvements in attention and change in cognition and ADL. In this multicenter, open-label, prospective study, patients with mild to moderate AD received galantamine and then submitted to computerized attention tests, the Alzheimer's Disease Assessment Scale-cognitive subscale, and instrumental ADL (IADL) at baseline, 4 weeks, and 12 weeks. The differences in reaction time on computerized tests were explored relative to the changes in cognition and IADL. After 12 weeks of taking the trial medication there was a significant reduction from baseline levels in the choice reaction time (baseline, 5,216±3,650 sec; 12 weeks, 4,139±2,920 sec; p<0.01) and the simple reaction time (baseline, 1,089±782 sec; 12 weeks, 908±606 sec; p<0.01). Correlation analyses of changes in choice or simple reaction times relative to cognition and ADL measures yielded no significant associations. The improvement in attention observed at 4 weeks of galantamine treatment was not associated with any significant changes in outcome measures at the end of trial. This study found no significant association between the improvement in attention after treatment with galantamine and changes in cognition and ADL in patients with mild to moderate AD, despite the significant improvement in attention over the course of the treatment.
    Full-text · Article · Jan 2015 · Journal of Clinical Neurology
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    Ji Young Jeon · Won-Jin Moon · Yeon-Sil Moon · Seol-Heui Han
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    ABSTRACT: Brain surface intensity model (BSIM)-based cortical thickness analysis does not require complicated 3D segmentation of brain gray/white matters. Instead, this technique uses the local intensity profile to compute cortical thickness. The aim of the present study was to evaluate intra-rater and inter-rater reliability of BSIM-based cortical thickness analysis using images from elderly participants.
    Full-text · Article · Jan 2015
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    ABSTRACT: The vascular depression hypothesis suggests that there is an association between cerebrovascular pathophysiology and depression in the elderly. We investigated depressive-like behaviors and perturbations in the hypothalamus-pituitary-adrenal (HPA) axis in a rat model of chronic cerebral hypoperfusion. We modeled chronic cerebral hypoperfusion by permanent occlusion of the bilateral common carotid arteries (BCCAo) in Wistar rats. Sucrose preference, forced swim, and social interaction tests were performed to measure depressive-like behaviors. The plasma levels of adrenocorticotropic hormone and corticosterone, and the hippocampal expression of the glucocorticoid receptor (GR) were assessed. Sucrose preference (P = 0.045) and social withdrawal (P = 0.038) were significantly enhanced in BCCAo rats. Increased plasma levels of corticosterone (P = 0.034) and impaired cytosolic-to-nuclear translocation of the GR protein were observed in the hippocampus (P = 0.038) of BCCAo rats. Our experimental results support the clinical hypothesis that vascular depression can be induced by chronic cerebral hypoperfusion. Increased HPA axis activity and perturbation of the GR signaling pathway in the hippocampus may be associated with depressive-like behaviors in rats with chronic cerebral hypoperfusion.
    No preview · Article · Dec 2014 · Translational Stroke Research
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    ABSTRACT: Males are predominantly affected by autism spectrum disorders (ASD) with a prevalence ratio of 5:1. However, the underlying pathological mechanisms governing the male preponderance of ASD remain unclear. Recent studies suggested that epigenetic aberrations may cause synaptic dysfunctions, which might be related to the pathophysiology of ASD. In this study, we used rat offspring prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found male-selective abnormalities in the kinetic profile of the excitatory glutamatergic synaptic protein expressions linked to N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4. Furthermore, VPA exposure showed a male-specific attenuation of the methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of offspring and in the gender-isolated neural progenitor cells (NPCs). In the gender-isolated NPCs culture, higher concentration of VPA induced an increased glutamatergic synaptic development along with decreased MeCP2 expression in both genders suggesting the role of MeCP2 in the modulation of synaptic development. In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA inhibited the MeCP2 expression in male- but not in female-derived NPCs with concomitant induction of postsynaptic proteins such as PSD95. Taken together, we suggest that the male-inclined reduction of MeCP2 expression is involved in the abnormal development of glutamatergic synapse and male preponderance in the VPA animal models of ASD.
    Full-text · Article · Nov 2014 · Molecular Neurobiology
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    ABSTRACT: Background & objective: Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. Methods: Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. Results: Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ε4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. Conclusion: Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.
    No preview · Article · Oct 2014 · Journal of Alzheimer's disease: JAD
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    ABSTRACT: Many patients with diabetes are at increased risk of cognitive dysfunction and dementia. Diabetes mellitus is a vascular risk factor that may increase the risk of dementia through its associations with vascular dementia. We tested whether cognitive impairment could be exacerbated in combined injury using a rat model of chronic cerebral hypoperfusion with diabetes. We also determined whether a potent inhibitor of type III phosphodiesterase could prevent the cognitive decline caused by this combined injury.
    No preview · Article · Oct 2014 · Neurobiology of Disease
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    ABSTRACT: Vascular dementia (VaD) is the second most common form of dementia caused by cerebrovascular disease. Several recent reports demonstrated that cholinergic deficits are implicated in the pathogenesis of VaD and that cholinergic therapies have shown improvement of cognitive function in patients with VaD. However, the precise mechanisms by which donepezil achieves its effects on VaD are not fully understood. Donepezil hydrochloride is an acetylcholinesterase inhibitor (AChEI) currently used for the symptomatic treatment of Alzheimer’s disease (AD). Several lines of evidence have demonstrated that AChEIs such as donepezil promote neurogenesis in the central nervous system. We investigated whether donepezil regulated hippocampal neurogenesis after bilateral common carotid artery occlusion (BCCAO), a commonly used animal model of VaD. To evaluate the effect of donepezil on neurogenesis, we orally treated rats with donepezil (10 mg/kg) once a day for 3 weeks, and injected BrdU over the same 3-week period to label newborn cells. The doses of donepezil we used have been reported to activate cholinergic activity in rats. After 3 weeks, a water maze task was performed on these rats to test spatial learning, and a subsequent histopathological evaluation was conducted. Donepezil improved memory impairment and increased the number of BrdU-positive cells in the dentate gyrus (DG) of BCCAO animals. These results indicated that donepezil improves cognitive function and enhances the survival of newborn neurons in the DG in our animal model of VaD, possibly by enhancing the expression of choline acetyltransferase and brain-derived neurotropic factor.
    No preview · Article · Sep 2014 · Journal of the Neurological Sciences
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    ABSTRACT: Valproic acid (VPA) with inhibitory activity of histone deacetylase has been used in the treatment of epilepsy and bipolar disorder that are associated with cerebrovascular dysfunction. Because nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a role in maintenance of vascular function, NO is likely to mediate VPA's drug effect, but its effect on NO production remains controversial. We investigated whether and how VPA regulates NO production in bovine aortic endothelial cells (BAEC) and mice. VPA increased NO production in BAEC, which was accompanied by decrease in phosphorylations of eNOS at serine 116 (eNOS-Ser(116)) and cyclin-dependent kinase 5 at tyrosine 15 (CDK5-Tyr(15)). Ectopic expression of p25, a CDK5 activator, restored the VPA-inhibited eNOS-Ser(116) phosphorylation. In silico analysis revealed that the CDK5-Tyr(15) residue might be a substrate for SH2 domain-containing protein tyrosine phosphatase 1 (SH-PTP1), and CDK5 actually interacted with SH-PTP1. VPA increased SH-PTP1 expression and its activity. Stibogluconate, a specific SH-PTP1 inhibitor, reversed the VPA-inhibited phosphorylations of CDK5-Tyr(15) and eNOS-Ser(116). Knockdown of SH-PTP1 using small interfering RNA also reversed all the observed VPA's effects. Finally, both serum NO level and acetylcholine-induced aortic relaxation increased in the VPA-medicated male mice. These increases were accompanied by increased SH-PTP1 expression and decreased phosphorylations of CDK5-Tyr(15) and eNOS-Ser(116) in mouse aortas. In conclusion, VPA increases NO production by inhibiting CDK5-Tyr(15)-eNOS-Ser(116) phosphorylation axis; this process is mediated by SH-PTP1. VPA may be useful in the treatment of NO-related cerebrocardiovascular diseases.
    No preview · Article · Aug 2014 · Free Radical Biology and Medicine
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    ABSTRACT: Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
    Full-text · Article · Aug 2014 · PLoS ONE

Publication Stats

929 Citations
504.76 Total Impact Points

Institutions

  • 2006-2015
    • Konkuk University
      • • Neuroscience Center
      • • Department of Psychiatry
      • • Department of Neurology
      • • School of Medicine
      Sŏul, Seoul, South Korea
  • 2009-2014
    • Konkuk University Medical Center
      • Department of Neurology
      창녕읍, Gyeongsangnam-do, South Korea
  • 2010
    • Hanyang University
      • Department of Biomedical Engineering
      Sŏul, Seoul, South Korea
  • 2003
    • Chungbuk National University
      • College of Medicine
      Chinsen, Chungcheongbuk-do, South Korea