Trichostatin A stimulates steroid 5alpha-reductase gene expression in rat C6 glioma cells via a mechanism involving Sp1 and Sp3 transcription factors.

Her, Song,Lee, Mi-Sook,Morita, Kyoji Birkhäuser Boston 2010 Journal of molecular neuroscience Vol.41 No.2

<P>The adrenergic and serotonergic stimulations of rat C6 glioma cells have previously been shown to induce the activation of steroid 5alpha-reductase (5alpha-R) gene expression, resulting in their differentiation through the production of neuroactive 5alpha-reduced steroid metabolites. In addition, progesterone and histone deacetylase (HDAC) inhibitors have also been reported to promote the glial cell differentiation with the enhancement of serotonin-stimulated brain-derived neurotrophic factor gene transcription through the production of 5alpha-reduced neurosteroids, thus suggesting that glial cell differentiation is probably implicated in the protection and survival of neuronal cells in the brain. Therefore, the expression of 5alpha-R gene in glial cells seems physiologically important in maintaining the neural function in the brain, but little is known about the mechanism underlying the regulation of 5alpha-R gene transcription. In the present study, the effect of a HDAC inhibitor trichostatin A (TSA) on 5alpha-R gene transcription in the glioma cells was examined, and TSA was shown to induce the elevation of 5alpha-R mRNA levels through the activation of the 5alpha-R promoter via a mechanism involving Sp1 and Sp3 transcription factors in a time- and concentration-dependent manner. Thus, both Sp1 and Sp3 are considered to play a physiological role in the regulation of 5alpha-R gene expression, and hence the production of 5alpha-reduced neurosteroids in glial cells.</P>

Effect of valproic acid through regulation of NMDA receptor-ERK signaling in sleep deprivation rats.

Park, Hae Jeong,Kang, Won Sub,Paik, Jong Woo,Kim, Jong Woo Birkhäuser Boston 2012 Journal of molecular neuroscience Vol.47 No.3

<P>Although the effect of mood stabilizer valproic acid (VPA) through multiple signaling pathways has been shown, its therapeutic mechanism is still largely unknown. We investigated the effect of VPA (200 mg/kg, every 12 h) in sleep deprivation (SD) rats (72 h), the manic-like animal model, focusing on the N-methyl-D: -aspartic acid (NMDA) receptor and signaling mediators of synaptic plasticity such as extracellular signal-regulated protein kinase (ERK), cAMP response element-binding protein (CREB), B cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and brain-derived neurotrophic factor (BDNF). SD reduced the expression of the NR2B subunit of the NMDA receptor in the frontal cortex and hippocampus but did not affect the expression of NR1 and NR2A subunits. In comparison, VPA inhibited the SD-induced reduction of NR2B expression in both brain regions. In addition, SD attenuated ERK phosphorylation in the frontal cortex and hippocampus, whereas VPA prevented the attenuation. VPA also protected the SD-induced decrease of CREB phosphorylation, BCL2 expression, and BDNF expression in the frontal cortex but not in the hippocampus. These results indicate that VPA could regulate NMDA receptor-ERK signaling in SD rats, preventing the SD-induced decrease of the expression of NR2B subunit and the activation of ERK signaling mediators such as ERK, CREB, BCL2, and BDNF.</P>

Association of Toll-like receptor 2 polymorphisms with National Institute of Health Stroke Scale scores of ischemic stroke patients.

Park, Hae Jeong,Kim, Su Kang,Yun, Dong Hwan,Kim, Dong Hwan,Chon, Jinmann,Kim, Jong Woo,Chung, Joo-Ho Birkhäuser Boston 2012 Journal of molecular neuroscience Vol.46 No.3

<P>Toll-like receptor 2 (TLR2) has been shown to have an important role in the postischemic inflammatory response and to contribute to ischemic brain damage. In this study, we investigated whether coding region single nucleotide polymorphisms (SNPs) of the TLR2 gene were associated with ischemic stroke (IS) and with clinical phenotypes in IS patients. We genotyped two SNPs (rs3804099 [Asn199Asn] and rs3804100 [Ser450Ser]) using direct sequencing in 202 IS patients and 291 control subjects. No SNPs of the TLR2 gene were found to be associated with IS. However, in analysis of clinical phenotypes, we found that rs3804099 was associated with the National Institute of Health Stroke Scale (NIHSS) scores of IS patients in codominant (TC vs. TT, p?=?0.0005; CC vs. TT, p?=?0.0007) and dominant models (TC/CC vs. TT, p?=?0.0001). Also, rs3804100 revealed significant association in codominant (TC vs. TT, p?=?0.0002; CC vs. TT, p?=?0.008) and dominant models (TC/CC vs. TT, p?<?0.0001). In allele frequency analysis, we also found that the C alleles of rs3804099 and rs3804100 were associated with higher NIHSS scores (p?=?0.0003 in rs3804099; p?=?0.0001 in rs3804100). Our results suggest that TLR2 may be related to severe IS.</P>

Possible relation of hemin-induced HO-1 expression to the upregulation of VEGF and BDNF mRNA levels in rat C6 glioma cells.

Morita, Kyoji,Lee, Mi-Sook,Her, Song Birkhäuser Boston 2009 Journal of molecular neuroscience Vol.38 No.1

<P>Glial cells are generally considered to contribute to retaining the integrity of neural function through the protection of neuronal cells against neurodegenerative insults and also expected to play a potential role in the protection of cerebrovascular systems from various toxic insults of hemorrhaged blood, thus proposing a possible implication of glial cells in the recovery of brain function from the damage caused by cerebral hemorrhage. Based on this hypothetical idea, the direct effect of hemin on the expression of genes encoding heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) in glial cells was examined using rat C6 glioma cells as an in vitro model system. Hemin elevated both HO-1 and VEGF mRNA levels in the glioma cells at the concentration causing no critical damage to the cells, and the elevation of BDNF mRNA levels was also observed by exposing the cells to hemin under the same conditions. Furthermore, the elevation of VEGF and BDNF mRNA levels induced by hemin was blocked by pretreatment of the cells with the agents inhibiting not only HO-1 gene expression but also its enzymatic activity. These pharmacological studies indicate that hemin can induce the enhancement of VEGF and BDNF gene expression probably through the mechanism mediated by HO-1 activity in the glioma cells, proposing the possibility that glial cells are capable of contributing to the recovery of brain function from the damage caused by cerebral hemorrhage through the production of neurogenic and angiogenic factors.</P>

Protective effect of carbamazepine on kainic acid-induced neuronal cell death through activation of signal transducer and activator of transcription-3.

Park, Hae Jeong,Kim, Su Kang,Chung, Joo-Ho,Kim, Jong Woo Birkhäuser Boston 2013 Journal of molecular neuroscience Vol.49 No.1

<P>Studies have shown that the protective effect of carbamazepine (CBZ) on seizure-induced neuronal injury. However, its precise mechanisms remain unknown. Here, to investigate the neuroprotective mechanism of CBZ against seizure-induced neuronal cell death, we identified the change of gene expressions by CBZ in the hippocampus of kainic acid (KA)-treated mice using microarray method, and studied the involvement of candidate gene in neuroprotective action of CBZ. KA (15?mg/kg) and/or CBZ (30?mg/kg, 0.5?h after KA exposure) were injected intraperitoneally into mice. Through microarray analysis, we found that signal transducer and activator of transcription-3 (Stat3) gene expression was upregulated in the hippocampal CA3 region, 24?h after KA injection (15?mg/kg), and that CBZ further elevated Stat3 expression in KA-treated mice. KA also increased the protein level and phosphorylation of Stat3, and CBZ further increased the Stat3 phosphorylation, without changing Stat3 protein level in KA-treated mice. In particular, phospho-Stat3 immunoreactivity (IR) by KA was shown in astrocytes rather than in neurons; whereas phospho-Stat3 IR by CBZ in KA-treated mice was observed predominantly in neurons, and also in neuroprotective protein Bcl-xL-expression cells. These results indicate that Stat3 may play an important role in neuroprotective action of CBZ on seizure-induced neuronal injury.</P>

Induction of NQO1 and Neuroprotection by a Novel Compound KMS04014 in Parkinson's Disease Models.

Son, Hyo Jin,Choi, Ji Hyun,Lee, Ji Ae,Kim, Dong Jin,Shin, Kye Jung,Hwang, Onyou Birkhäuser Boston 2015 Journal of molecular neuroscience Vol.56 No.2

<P>Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Lines of evidence suggest that oxidative stress is a major factor contributing to the vulnerability of DA cells and that the enzyme NAD(P)H quinone oxidoreductase (NQO1) provides protection in these cells. In the present study, we report the synthesis of a novel compound KMS04014 and show that it induces NQO1 gene expression and protects DAergic neuronal cells in both cell culture and animal models of PD. In vitro, KMS04014 increased both mRNA and protein levels of NQO1 and induced nuclear translocation of Nrf2 in the DAergic neuronal cell line CATH.a. It also protected the cells against oxidative stress generated by tetrahydrobiopterin, 1-methyl-4-phenylpyridinium (MPP(+)), and H2O2. In vivo, KMS04014 attenuated the loss of tyrosine hydroxylase-immunopositive DAergic neurons in the substantia nigra and reduced degeneration of the nigral neurons and striatal fibers in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an animal model of PD. Taken together, KMS04014 may be utilized toward development of neuroprotective therapy for PD.</P>

Protective function of nicotinamide against ketamine-induced apoptotic neurodegeneration in the infant rat brain.

Ullah, Najeeb,Ullah, Ikram,Lee, Hae Young,Naseer, Muhammad Imran,Seok, Park Moon,Ahmed, Jawad,Kim, Myeong Ok Birkhäuser Boston 2012 Journal of molecular neuroscience Vol.47 No.1

<P>During development, anesthetics activate neuroapoptosis and produce damage in the central nervous system that leads to several types of neurological disorders. A single dose of ketamine (40?mg/kg) during synaptogenesis in a 7-day-old rat brain activated the apoptotic cascade and caused extensive neuronal cell death in the forebrain. In this study, we investigated the protective effect of nicotinamide against ketamine-induced apoptotic neurodegeneration. After 4?h, neuronal cell death induced by ketamine was associated with the induction of Bax, release of cytochrome c into the cytosol, and activation of caspase-3. One single dose of 1?mg/g nicotinamide was administered to a developing rat and was found to inhibit ketamine-induced neuroapoptosis by downregulating Bax, inhibiting cytochrome c release from mitochondria into cytosol, and inhibiting the expression of activated caspase-3. TUNEL and immunohistochemical analyses showed that ketamine-induced cell death occurred through apoptosis and that it was inhibited by nicotinamide. Fluoro-Jade-B staining demonstrated an increased number of dead cells in the cortex and thalamus after ketamine treatment; treatment with nicotinamide reduced the number of dead cells in these brain regions. Our findings suggest that nicotinamide attenuated ketamine-induced neuronal cell loss in the developing rat brain and is a promising therapeutic and neuroprotective agent for the treatment of neurodevelopmental disorders.</P>

Global transcriptome profiling of genes that are differentially regulated during differentiation of mouse embryonic neural stem cells into astrocytes.

Han, Dalmuri,Choi, Mi Ran,Jung, Kyoung Hwa,Kim, Namshin,Kim, Se Kye,Chai, Jin Choul,Lee, Young Seek,Chai, Young Gyu Birkhäuser Boston 2015 Journal of molecular neuroscience Vol.55 No.1

<P>Many genes are associated with the differentiation of neural stem cells (NSCs) into astrocytes, the most abundant and functionally diverse population of glial cells in the central nervous system, particularly in the brain. In the present study, we differentiated NSCs from the forebrain of embryonic day 14.5 mouse embryos into astrocytes over 1 and 7 days. We identified transcriptomes of NSCs and astrocytes using RNA sequencing and analyzed enriched gene networks, signal pathways, and ontology. To identify important regulators of differentiation, we performed gene clustering according to expression patterns and promoter CG types. Our data show that genes related to system development, including Fbln2, Bcan, Ncam1, Itih3, Tnr, and Vcan, regulate NSC differentiation through WNT/beta-catenin and epithelial to mesenchymal transition pathways. We identified many CG-rich promoter genes related to basic cellular maintenance such as transcription, translation, and structural components and CG-poor promoter genes that are highly associated with cell-type-specific functions or play important roles during development. Our study provides a foundation for further research on NSC differentiation and the future application of stem cells.</P>

Progesterone pretreatment enhances serotonin-stimulated BDNF gene expression in rat c6 glioma cells through production of 5alpha-reduced neurosteroids.

Morita, Kyoji,Her, Song Birkhäuser Boston 2008 Journal of molecular neuroscience Vol.34 No.3

<P>Tricyclic antidepressants and selective serotonin reuptake inhibitors are considered in theory to induce the outflow of neurotransmitters, norepinephrine, and serotonin from the synapses as a consequence of inhibiting their reuptake into the nerve terminals, resulting in the stimulation of glial cells surrounding the synapses in the brain. Then, we have investigated the direct actions of neurotransmitters on glial cell metabolism and function using rat C6 glioma cells as an in vitro model system and suggested that these neurotransmitters induce their differentiation probably through the production of 5alpha-reduced neurosteroids. On the other hand, the stimulation of the glioma cells with serotonin has been reported to enhance brain-derived neurotrophic factor (BDNF) gene expression, which may be closely related to the beneficial effects of antidepressant drugs. In the present study, to evaluate BDNF expression in differentiated glial cells, the glioma cells were pretreated with progesterone, and the effect of serotonin on BDNF messenger RNA levels in these cells was examined. Progesterone pretreatment enhanced the stimulatory action of serotonin on BDNF gene expression, and the enhancement of serotonin action observed in the cells pretreated with progesterone was almost completely abolished by finasteride, an inhibitor of the enzyme involved in the production of 5alpha-reduced neurosteroids. These findings propose the possibility that neurosteroid-mediated glial cell differentiation may result in the enhancement of serotonin-stimulated BDNF gene expression, which is considered to contribute to the survival, regeneration, and plasticity of neuronal cells in the brain, and hence, leading to the improvement of mood disorders and other symptoms in depressive patients.</P>