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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; · 4.06 Impact Factor
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Kyu Suk Cho,
So Hyun Joo,
Chang Soon Choi,
Ki Chan Kim,
Hyun Myung Ko,
Jin Hee Park,
Pitna Kim,
Jun Hur,
Sung Hoon Lee,
Geon Ho Bahn,
Jong Hoon Ryu,
Jongmin Lee,
Seol-Heui Han,
Kyoung Ja Kwon, Chan Young Shin
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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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Xiaotong Liu,
Sung In Hong,
Se Jin Park,
June Bryan Dela Peña,
Haiyan Che,
Seo Young Yoon,
Dong Hyun Kim,
Jong Min Kim,
Mudan Cai,
Victoria Risbrough,
Mark A Geyer, Chan Young Shin,
Jae Hoon Cheong,
Haeil Park,
Jae Hwan Lew,
Jong Hoon Ryu
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ABSTRACT: We previously reported that oroxylin A, a γ-aminobutyric acid A (GABAA) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-D-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 μM) inhibited intracellular Cl(-) influx induced by muscimol, a selective GABAA receptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system.
Archives of Pharmacal Research 03/2013; · 1.59 Impact Factor
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Kyu Suk Cho,
Kyoung Ja Kwon,
Chang Soon Choi,
Se Jin Jeon,
Ki Chan Kim,
Jin Hee Park,
Hyun Myung Ko,
Sung Hoon Lee,
Jae Hoon Cheong,
Jong Hoon Ryu,
Seol Heui Han, Chan Young Shin
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ABSTRACT: Tissue plasminogen activator (tPA) is expressed in several regions of brain and plays regulatory roles such as neurite outgrowth, synaptic plasticity and long term potentiation. The activity of tPA is regulated by an endogenous inhibitor plasminogen activator inhibitor-1 (PAI-1), which is expressed mainly in astrocytes. Valproic acid (VPA), a histone deacetylase inhibitor that is used for the treatment of epilepsy and bipolar disorders, promotes neurite extension, neuronal growth and has neuroprotective effect in neurodegenerative diseases. In this study, we examined whether the neurite extension effects of VPA is mediated by modulating tPA/PAI-1 system. VPA dose-dependently increased tPA activity and decreased PAI-1 activity in rat primary astrocytes but not in neurons. PAI-1 protein level secreted into the culture medium but not tPA per se was decreased by VPA. In co-culture system or in neuronal culture stimulated with astrocyte conditioned media but not in pure neuronal cell culture, VPA induced neurite outgrowth via increased tPA activity due to the decreased PAI-1 activity in astrocytes. The decrease in PAI-1 activity and increased neurite extension was regulated via JNK mediated post-transcriptional pathway. The essential role of tPA/PAI-1 system in the regulation of VPA-mediated neurite extension was further demonstrated by experiments using astrocyte conditioned media obtained from tPA or PAI-1 knockout mice. Regulation of PAI-1 activity in astrocyte by VPA may affect both physiological and pathological processes in brain by upregulating tPA activity. GLIA 2013.
Glia 02/2013; · 4.82 Impact Factor
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Seo Young Yoon,
Ike Dela Peña,
Sung Mok Kim,
Tae Sun Woo, Chan Young Shin,
Kun Ho Son,
Haeil Park,
Yong Soo Lee,
Jong Hoon Ryu,
Mingli Jin,
Kyeong-Man Kim,
Jae Hoon Cheong
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ABSTRACT: In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD.
Archives of Pharmacal Research 01/2013; · 1.59 Impact Factor
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Se Jin Park,
Se Jin Jeon,
Ike C Dela Peña,
Hyung Eun Lee,
Dong Hyun Kim,
Jong Min Kim,
Young Woo Lee,
Jun Man Jung,
Bum Young Shin,
Seungheon Lee,
Jae Hoon Cheong, Chan Young Shin,
Dae Sik Jang,
Jong Hoon Ryu
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ABSTRACT: Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-β, and phosphorylated cAMP response element-binding protein levels in the cortex and hippocampus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-β levels induced by MK-801 in the cortex but not in the hippocampus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801. Copyright © 2013 John Wiley & Sons, Ltd.
Phytotherapy Research 01/2013; · 2.09 Impact Factor
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Ki Chan Kim,
Pitna Kim,
Hyo Sang Go,
Chang Soon Choi,
Jin Hee Park,
Hee Jin Kim,
Se Jin Jeon,
Ike Campomayor Dela Pena,
Seol-Heui Han,
Jae Hoon Cheong,
Jong Hoon Ryu, Chan Young Shin
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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; · 4.06 Impact Factor
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Kyoung Ja Kwon,
Jung Nam Kim,
Min Kyeong Kim,
Su Young Kim,
Kyu Suk Cho,
Se Jin Jeon,
Hahn Young Kim,
Jong Hoon Ryu,
Sun-Young Han,
Jae Hoon Cheong,
Louis J Ignarro,
Seol-Heui Han, Chan Young Shin
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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; · 2.86 Impact Factor
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Pitna Kim,
Jin Hee Park,
Chang Soon Choi,
Inah Choi,
So Hyun Joo,
Min Kyoung Kim,
Soo Young Kim,
Ki Chan Kim,
Seung Hwa Park,
Kyoung Ja Kwon,
Jongmin Lee,
Seol-Heui Han,
Jong Hoon Ryu,
Jae Hoon Cheong,
Jung Yeol Han,
Ki Narm Ko, Chan Young Shin
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ABSTRACT: Prenatal exposure to alcohol has consistently been associated with adverse effects on neurodevelopment, which is collectively called fetal alcohol spectrum disorder (FASD). Increasing evidence suggest that prenatal exposure to alcohol increases the risk of developing attention deficit/hyperactivity disorder-like behavior in human. In this study, we investigated the behavioral effects of prenatal exposure to EtOH in offspring mice and rats focusing on hyperactivity and impulsivity. We also examined changes in dopamine transporter and MeCP2 expression, which may underlie as a key neurobiological and epigenetic determinant in FASD and hyperactive, inattentive and impulsive behaviors. Mouse or rat offspring born from dam exposed to alcohol during pregnancy (EtOH group) showed hyper locomotive activity, attention deficit and impulsivity. EtOH group also showed increased dopamine transporter and norepinephrine transporter level compared to control group in the prefrontal cortex and striatum. Prenatal exposure to EtOH also significantly decreased the expression of MeCP2 in both prefrontal cortex and striatum. These results suggest that prenatal exposure to EtOH induces hyperactive, inattentive and impulsive behaviors in rodent offspring that might be related to global epigenetic changes as well as aberration in catecholamine neurotransmitter transporter system.
Neurochemical Research 01/2013; · 2.24 Impact Factor
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ABSTRACT: Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, Red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dosedependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 10/2012; · 2.99 Impact Factor
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ABSTRACT: Since the development of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, this procedure has been specifically used for analyzing proteins or high molecular weight compounds because of the interference of matrix signals in the regions of the low mass range. Recently, scientists have been using a wide range of chemical compounds as matrices that ionize small molecules in a mass spectrometer and overcome the limitations of MALDI mass spectrometry. In this study, we developed a new combination matrix of 3-hydroxycoumarin (3-HC) and 6-aza-2-thiothymine (ATT), which is capable of ionizing small molecules, including drugs and single amino acids. In addition to ionization of small molecules, the combination matrix by itself gives less signals in the low mass region and can be used for performing imaging mass spectrometry (IMS) experiments on tissues, which confirms the vacuum stability of the matrix inside a MALDI chamber. The drug donepezil was mapped in the intact tissue slices of mice simultaneously with a spatial resolution of 150 μm during IMS. IMS analysis clearly showed that intact donepezil was concentrated in the cortical region of the brain at 60 min after oral administration. Our observations and results indicate that the new combination matrix can be used for analyzing small molecules in complex samples using MALDI mass spectrometry.
The Analyst 10/2012; · 4.23 Impact Factor
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Hyo Sang Go,
Ki Chan Kim,
Chang Soon Choi,
Se Jin Jeon,
Kyung Ja Kwon,
Seol-Heui Han,
Jongmin Lee,
Jae Hoon Cheong,
Jong Hoon Ryu,
Chong-Hyun Kim,
Kwang Ho Ko, Chan Young Shin
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ABSTRACT: Autism is a spectrum of neurodevelopmental disorders characterized by social isolation and lack of interaction. Anatomically, autism patients often show macrocephaly and high neuronal density. To investigate the mechanism underlying the higher neuronal populations seen in ASD, we subcutaneously injected VPA (400 mg/kg) into pregnant Sprague-Dawley rats on E12, an animal model often used in ASD study. Alternatively, cultured rat neural progenitor cells were treated with VPA. Until E18, VPA induced NPC proliferation and delayed neurogenesis in fetal brain, but the subsequent differentiation of NPCs to neurons increased brain neuronal density afterward. Similar findings were observed with NPCs treated with VPA in vitro. At a molecular level, VPA enhanced Wnt1 expression and activated the GSK-3β/β-catenin pathway. Furthermore, inhibition of this pathway attenuated the effects of VPA. The findings of this study suggest that an altered developmental process underlies the macrocephaly and abnormal brain structure observed in the autistic brain.
Neuropharmacology 07/2012; 63(6):1028-41. · 4.81 Impact Factor
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Se Jin Jeon,
Seol-Heui Han,
Sung-Il Yang,
Ji Woong Choi,
Kyoung Ja Kwon,
Seung Hwa Park,
Hahn Young Kim,
Jae Hoon Cheong,
Jong Hoon Ryu,
Kwang Ho Ko,
David G Wells, Chan Young Shin
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ABSTRACT: J. Neurochem. (2012) 123, 226-238. ABSTRACT: Fragile X syndrome (FXS), the most common single genetic cause of mental retardation and autistic spectrum disease, occurs when FMR1 gene is mutated. FMR1 encodes fragile X mental retardation protein (FMRP) which regulates translation of mRNAs playing important roles in the development of neurons as well as formation and maintenance of synapses. To examine whether FMRP regulates cell viability, we induced apoptosis in rat primary cortical neurons with glutamate in vitro and with middle cerebral artery occlusion (MCAO) in striatal neurons in vivo. Both conditions elicited a rapid, but transient FMRP expression in neurons. This up-regulated FMRP expression was abolished by pre-treatment with PI3K and Protein Kinase B (Akt) inhibitors: LY294002, Akt inhibitor IV, and VIII. Reduced FMRP expression in vitro or in vivo using small hairpin Fmr1 virus exacerbated cell death by glutamate or MCAO, presumably via hypophosphorylation of Akt and reduced expression of B-cell lymphoma-extra large (Bcl-xL). However, over-expression of FMRP using enhanced green fluorescent protein (eGFP)-FMRP constructs alleviated cell death, increased Akt activity, and enhanced Bcl-xL production. The pro-survival role of Akt-dependent up-regulation of FMRP in glutamate-stimulated cultured neuron as well as in ischemic brain may have a clinical importance in FXS as well as in neurodegenerative disorders and traumatic brain injury.
Journal of Neurochemistry 07/2012; 123(2):226-238. · 4.06 Impact Factor
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ABSTRACT: Neuronal membrane phospholipids are highly affected by oxidative stress caused by ischemic injury. Thus, it is necessary to identify key lipid components that show changes during ischemia to develop an effective approach to prevent brain damage from ischemic injury. The recent development of MALDI imaging MS (MALDI IMS) makes it possible to identify phospholipids that change between damaged and normal regions directly from tissues. In this study, we conducted IMS on rat brains damaged by ischemic injury and detected various phospholipids that showed unique distributions between normal and damaged areas of the brain. Among them, we confirmed changes in phospholipids such as lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin by MALDI IMS followed by MS/MS analysis. These lipids were present in high concentrations in the brain and are important for maintenance of cellular structure as well as production of second messengers for cellular signal transduction. Our results emphasize the identification of phospholipid markers for ischemic injury and successfully identified several distinctly located phospholipids in ischemic brain tissue.
The Journal of Lipid Research 06/2012; 53(9):1823-31. · 5.56 Impact Factor
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ABSTRACT: The aim of this study was to investigate whether vitamin C influences the stress response system of the adrenal gland. Adrenalectomized
(ADX) rats and non-ADX rats were administered vitamin C and were subjected to electroshock stress (ES) for 5 days. After loading
the final stress, stress-related behaviors and corticosterone (CORT), vitamin C, and adrenocorticotropin-releasing hormone
(ACTH) levels in the blood were measured. Vitamin C supplementation decreased CORT levels in non-ADX rats. Stress decreased
the mean value of rearing frequency in both non-ADX and ADX rats, while vitamin C partially enhanced it only in non-ADX. Vitamin
C supplementation decreased mean ACTH level in both groups. It also significantly decreased freezing time increased by stress.
Lastly, vitamin C motivated both groups to cross over an electric field more frequently as compared to their respective control
groups. These results suggest that the alleviating effect of vitamin C on stress-related rearing behavior was exerted via
modulation of CORT, but its effect on freezing behavior may be attributed to corticotropin-releasing hormone (CRH) or ACTH.
Keywordsvitamin C–electroshock stress–corticosterone–behavior
Food science and biotechnology 05/2012; 20(2):429-435. · 0.49 Impact Factor
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ABSTRACT: In the present study, we investigated the possible mechanisms of cellular injury induced by zinc in rat primary astrocytes
and C6 glioma cells. Reactive oxygen species (ROS) production, cellular glutathione (GSH) level and mitochondrial transmembrane
potential were examined. Exposure to 200–300 μM Zn2+ for 24 h resulted in significant lactate dehydrogenase (LDH) release in rat primary astrocytes and C6 glioma cells. An exposure
of 200 μM Zn2+ resulted in profound morphological changes, for example, shrunken and fragmented nuclei. Pretreatment of a protein synthesis
inhibitor, cycloheximide, did not attenuate cellular toxicity induced by Zn2+. Zn2+ exposure increased intracellular ROS levels by about 250%, and depleted cellular GSH within 2 h, which preceded observable
LDH release from the cell. Addition of GSH, N-acetylcysteine (NAC) and ascorbic acid substantially attenuated cellular death induced by Zn2+ in a concentration dependent manner. ROS production and morphological changes induced by zinc were also inhibited by co-treatment
of GSH or NAC with Zn2+. Zn2+ significantly depolarized mitochondrial transmembrane potential, which was reversed by co-treatment of GSH or NAC with zinc.
In summary, ROS generation, GSH depletion and mitochondrial dysfunction may be key factors in Zn2+-induced glial toxicity.
Experimental Brain Research 04/2012; 143(2):257-263. · 2.39 Impact Factor
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ABSTRACT: The aim of this study was to investigate what kind of stress vitamin C could alleviate. Experiments were performed using male
ICR mice. Vitamin C (1, 5, 25, and 100 mg/kg) was administered orally daily for 7 days without stress and then were given
for 5 days with electroshock (ES) or restraint stress (RS). After loading final stress, we recorded stress-related behaviors
and measured the levels of blood corticosterone. Vitamin C supplementation (25 and 100 mg/kg) partially blocked stress-related
behaviors such as freezing, smelling, burrowing, facewashing, and grooming. It decreased also staying time in closed arms.
Stress responses induced by ES but not immobility were also significantly alleviated by vitamin C. Vitamin C (25 and 100 mg/kg)
decreased corticosterone level increased by ES. Swimming time in cold water (8±2°C) was not changed by vitamin C, but crossing
frequency in the electric field was increased by vitamin C (25 mg/kg). These results suggest that vitamin C supplementation
can prevent damages or diseases induced by stress, especially psychological stress.
Keywordsvitamin C-electro-shock stress-restraint stress-behavior-corticosterone
Food science and biotechnology 04/2012; 19(1):137-144. · 0.49 Impact Factor
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ABSTRACT: Available evidence strongly suggests that the γ-aminobutyric acid type A (GABA(A)) receptor has a crucial role in memory retrieval. However, the signaling mechanisms underlying the role of GABA(A) receptor modulation in memory retrieval are unclear. We conducted one-trial passive avoidance task with pre-retention trial drug administration in the hippocampus to test the effects of GABA(A) receptor modulation on memory retrieval. We further tested the co-involvement of signaling molecules: extracellular signal-regulated kinase (ERK), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and cAMP responsive element-binding protein (CREB). First, we observed that the phosphorylation of hippocampal ERK was required for memory retrieval during the task. Accordingly, to investigate whether GABA(A) receptor activation or inhibition induces ERK phosphorylation during memory retrieval, drugs that target the GABA(A) receptor were administered into the hippocampus before the retention trial. Muscimol, a GABA(A) receptor agonist, and diazepam, an agonist to benzodiazepine-binding site of GABA(A) receptor, blocked retention trial-induced ERK phosphorylation and impaired memory retrieval. Furthermore, co-treatment with sub-effective dose of U0126, a mitogen-activated protein kinase inhibitor, blocked the upregulation of ERK phosphorylation and impaired memory retrieval, and bicuculline methiodide (BMI), a GABA(A) receptor antagonist, increased ERK phosphorylation induced by the retention trial and facilitated memory retrieval. Finally, the effects of BMI were blocked by the co-application of a sub-effective dose of U0126. These results suggest that GABA(A) receptor-mediated memory retrieval is closely related to ERK activity.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2011; 37(5):1234-44. · 6.99 Impact Factor
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ABSTRACT: Methylphenidate is a psychostimulant given for extended periods of time as a treatment of attention-deficit/hyperactivity disorder (ADHD). The long-term effects of the drug are not yet known, and it is speculated that repeated exposure may produce drug dependence.
To investigate the effects of repeated methylphenidate treatment on methylphenidate self-administration and reinstatement in the most validated animal model of ADHD, the spontaneously hypertensive rat (SHR), and Wistar rat, strain representing the "normal" heterogeneous population.
Rats were administered intraperitoneally with saline or methylphenidate (2 mg/kg) for 14 days, prior to experiments. Thereafter, responses for intravenous methylphenidate under the fixed ratio (FR1 and FR3) and progressive ratio (PR) schedules were assessed. Extinction experiments followed, as well as tests to determine the ability of intraperitoneal administration of methylphenidate (2 and 5 mg/kg) to reinstate extinguished drug-seeking behaviors in rats.
Previous exposure to methylphenidate enhanced methylphenidate self-administration in Wistar rats but not in SHR (FR3). Methylphenidate pretreatment reduced responding for methylphenidate in SHR but did not affect self-administration behaviors of Wistar rats (PR). Methylphenidate pre-exposure robustly reinstated drug-seeking behaviors in Wistar rats, but not in SHR.
The contrasting effects of repeated methylphenidate treatment in methylphenidate self-administration and reinstatement in Wistar and SHR, and the increased susceptibility of the Wistar rat strain to the reinforcing effects of methylphenidate indicate that "normal" individuals are more likely to develop psychological dependence to the drug and experience relapse. Meanwhile, the clinical use of methylphenidate may not produce drug dependence or relapse in ADHD patients.
Psychopharmacologia 11/2011; 221(2):217-26. · 4.08 Impact Factor
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ABSTRACT: Memory consolidation is the process by which acquired information is converted to something concrete to be retrieved later. Here we examined a potential role for brain-derived neurotrophic factor (BDNF) in mediating the enhanced memory consolidation induced by the GABA(A) receptor antagonist, bicuculline methiodide. With the administration of an acquisition trial in naïve mice using a passive avoidance task, mature BDNF (mBDNF) levels were temporally changed in the hippocampal CA1 region, and the lowest levels were observed 9 h after the acquisition trial. In the passive avoidance task, bicuculline methiodide administration within 1 h of training but not after 3 h significantly increased latency time in the retention trial 24 h after the acquisition trial. Concomitantly, 1 h post-training administration of bicuculline methiodide, which enhanced memory consolidation, significantly increased mBDNF levels 9 h after training compared to those of the vehicle-treated control group. In addition, exogenous human recombinant BDNF (hrBDNF) administration 9 h after training into the hippocampal CA1 region facilitated memory consolidation confirming that the increase in mBDNF at around 9 h after training plays a key role in the enhancement of memory consolidation. Moreover, the increases in latency time and immediate early gene expressions by bicuculline methiodide or hrBDNF were significantly blocked by anisomycin, a protein synthesis inhibitor, K252a, a tyrosine receptor kinase (Trk) inhibitor, or anti-TrkB IgG. These findings suggest that the increase in the level of mBDNF and its function during a restricted time window after training are required for the enhancement of memory consolidation by GABA(A) receptor blockade.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2011; 37(2):422-33. · 6.99 Impact Factor
