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At least 991 records · Page 55Linked to original sources
PubMed2006

Chronic valproic acid treatment triggers increased neuropeptide y expression and signaling in rat nucleus reticularis thalami.

Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administration to young rats (300-600 mg.kg(-1).d(-1) in divided doses over 4 d) resulted in a 30-50% increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmunoassay, and immunohistochemistry. No increased expression was observed after a single acute dose of VPA. Chronic treatment with the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for the mRNAs of the Y1 receptor or of the neuropeptides somatostatin, vasoactive intestinal polypeptide, and choleocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepileptic actions of chronic VPA therapy.

Action Potentials↗
PubMed2004

Improving the survival of human CNS precursor-derived neurons after transplantation.

We have examined the effects of predifferentiation and energy substrate deprivation on long-term expanded human neural precursor cells (HNPCs). The pre-differentiation of HNPC cultures produced large numbers of neurons (>60%) and mature glial cells capable of generating glycogen stores that protected the neuronal population from experimental metabolic stress. When predifferentiated HNPCs were transplanted into intact adult rat hippocampus, fewer cells survived compared to undifferentiated HNPC transplants. This cell death was completely attenuated, however, when predifferentiated HNPC cultures were pretreated to boost glial energy stores and resulted in greatly increased neuronal survival in vivo. The transplanted cells primarily engrafted within the granular layer of the dentate gyrus, where a large proportion of the predifferentiated HNPCs co-expressed neuronal markers whereas most HNPCs outside of the neuronal layer did not, indicating that the predifferentiated cells remained capable of responding to local cues in the adult brain. Undifferentiated HNPCs migrated more widely in the brain after grafting than did the predifferentiated cells, which generally remained within the hippocampus.

Analysis of Variance↗
PubMed2005

Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system.

To explore the role of DNA methylation in the brain, we examined the expression pattern of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the mouse central nervous system (CNS). By comparing the levels of Dnmt3a and Dnmt3b mRNAs and proteins in the CNS, we showed that Dnmt3b is detected within a narrow window during early neurogenesis, whereas Dnmt3a is present in both embryonic and postnatal CNS tissues. To determine the precise pattern of Dnmt3a and Dnmt3b gene expression, we carried out X-gal histochemistry in transgenic mice in which the lacZ marker gene is knocked into the endogenous Dnmt3a or Dnmt3b gene locus (Okano et al. [1999] Cell 99:247-257). In Dnmt3b-lacZ transgenic mice, X-gal-positive cells are dispersed across the ventricular zone of the CNS between embryonic days (E) 10.5 and 13.5 but become virtually undetectable in the CNS after E15.5. In Dnmt3a-lacZ mice, X-gal signal is initially observed primarily in neural precursor cells within the ventricular and subventricular zones between E10.5 and E17.5. However, from the newborn stage to adulthood, Dnmt3a X-gal signal was detected predominantly in postmitotic CNS neurons across all the regions examined, including olfactory bulb, cortex, hippocampus, striatum, and cerebellum. Furthermore, Dnmt3a signals in CNS neurons increase during the first 3 weeks of postnatal development and then decline to a relatively low level in adulthood, suggesting that Dnmt3a may be of critical importance for CNS maturation. Immunocytochemistry experiments confirmed that Dnmt3a protein is strongly expressed in neural precursor cells, postmitotic CNS neurons, and oligodendrocytes. In contrast, glial fibrillary acidic protein-positive astrocytes exhibit relatively weak or no Dnmt3a immunoreactivity in vitro and in vivo. Our data suggest that whereas Dnmt3b may be important for the early phase of neurogenesis, Dnmt3a likely plays a dual role in regulating neurogenesis prenatally and CNS maturation and function postnatally.

Animals↗
PubMed2005

Counteraction by repetitive daily exposure to static magnetism against sustained blockade of N-methyl-D-aspartate receptor channels in cultured rat hippocampal neurons.

In rat hippocampal neurons cultured with the antagonist for N-methyl-D-aspartate (NMDA) receptors dizocilpine (MK-801) for 8 days in vitro (DIV), a significant decrease was seen in the expression of microtubule-associated protein-2 (MAP-2) as well as mRNA for both brain-derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43), in addition to decreased viability. MK-801 not only decreased the expression of the NR1 subunit of NMDA receptors but also increased NR2A expression, without affecting NR2B expression. Repetitive daily exposure to static magnetic fields at 100 mT for 15 min led to a decrease in the expression of MAP-2, without significantly affecting cell viability or the expression of neuronal nuclei (NeuN) and GAP-43. However, the repetitive magnetism prevented decreases in both BDNF mRNA and MAP-2 and additionally increased the expression of NR2A subunit, without altering NR1 expression in neurons cultured in the presence of MK-801. Repetitive magnetism was also effective in preventing the decrease by MK-801 in the ability of NMDA to increase intracellular free Ca2+ ions, without affecting the decrease in the maximal response. These results suggest that repetitive magnetism may at least in part counteract the neurotoxicity of MK-801 through modulation of the expression of particular NMDA receptor subunits in cultured rat hippocampal neurons.

Analysis of Variance↗
PubMed2005

Cerebral neurocytoma without ganglion cell differentiation.

Neurocytomas are rare neuronal tumours, and are defined as tumours comprising cells with neuronal differentiation; they commonly arise in the ventricles. We report a case of a cerebral neurocytoma in a young man who presented with hemiparesis. The tumour was a radiologically a well-circumscribed large cyst with solid mass; the histopathology showed a well-differentiated lesion comprising uniform, round cells with perinuclear halos in a neuropil background, and immunohistochemically positive for neuronal markers (synaptophysin, neuron-specific enolase and neurofilaments). We suggest that cerebral neurocytomas should be considered among the uncommon causes of a large intra-axial cystic mass with a solid component in young adults.

Adult↗
PubMed1989

Strong-cation-exchange sulfoethyl aspartamide chromatography for peptide mapping of Staphylococcus aureus V8 protein digests.

In two recent reports (D. L. Crimmins, J. Gorka, R. S. Thoma, and B. D. Schwartz (1988) J. Chromatogr. 443, 63-71; A. J. Alpert and P. C. Andrews (1988) J. Chromatogr. 443, 85-96) a sulfoethyl aspartamide column was shown to efficiently analyze peptides less than 25 residues in length which differ in the number of nominal positive charges at pH 3.0. In particular, the elution order for a series of distinct peptides ranging in nominal charge from +1 to +7 was found to be monotonic in nature indicating that separation was primarily via a cation-exchange mechanism. The present study employs this chromatographic system to isolate and characterize major fragments of proteolytic digests. Six commercially available proteins of known sequence (myoglobin, beta-casein, concanavalin A, carbonic anhydrase, lentil lectin, and enolase) were digested with Staphylococcus aureus V8 to generate peptide fragments. The resulting mixture was chromatographed on a sulfoethyl aspartamide column to isolate major fragments which were then subjected to amino acid analysis and N-terminal sequencing. With complete proteolysis (i.e., peptide fragments terminating in either an aspartic or a glutamic acid) separation of the fragments should result from the sum of histidine, lysine, and arginine residues contained in each fragment. Most of the peptide fragments eluted at the expected time on the sulfoethyl aspartamide column. Those fragments with anomalous behavior resulted from incomplete cleavage or cleavage at nonacidic residues or were greater than 35 residues in length. Each proteolytic digest was also analyzed by standard reverse-phase C4 chromatography to compare the peptide maps for these two distinct chromatographic modes.

Alkanesulfonates↗
PubMed1992

Adriamycin promotes neurite outgrowth in the "neurite-minus" N1A-103 mouse neuroblastoma cell line.

Adriamycin, an anticancer agent acting on topoisomerase II, promotes the arrest of cell division and neurite extension in a "neurite-minus" murine neuroblastoma cell line, N1A-103. This morphological differentiation is accompanied by a blockade in the S phase of the cell cycle, modification of the amount of peripherin, and appearance of the beta 7-tubulin isoform. Yet, adriamycin-induced N1A-103 cells fail to express other neuronal markers, such as long-lasting Ca2+ channels, synaptophysin, and the shift in the proportion of the beta'1 tubulin isoform to the beta'2 isoform, whose appearance parallels the terminal differentiation of the wild type neuroblastoma cell line N1E-115. Hence, a comparison of the behavior of these two cell lines leads to the proposal that there are two programs of neuroblastoma differentiation: one where expression is triggered by the arrest of cell division and which is observed in adriamycin-induced N1A-103 variant cells, and the other, presumably occurring further downstream, which would involve further changes in morphogenesis and acquisition of new electrophysiological properties.

Animals↗
PubMed2005

Signaling pathways of interleukin-1 actions in the brain: anatomical distribution of phospho-ERK1/2 in the brain of rat treated systemically with interleukin-1beta.

Interleukin-1beta is released at the periphery during infection and acts on the nervous system to induce fever, neuroendocrine activation, and behavioral changes. These effects are mediated by brain type I IL-1 receptors. In vitro studies have shown the ability of interleukin-1beta to activate mitogen-activated protein kinase signaling pathways including p38, c-Jun N-terminal kinase and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). In contrast to other mitogen-activated protein kinases, little is known about ERK1/2 activation in the rat brain in response to interleukin-1beta. The aim of the present study was therefore to investigate spatial and temporal activation of ERK1/2 in the rat brain after peripheral administration of interleukin-1beta using immunohistochemistry to detect the phosphorylated form of the kinase. In non-stimulated conditions, phosphorylated ERK1/2 immunoreactivity was observed in neurons throughout the brain. Administration of interleukin-1beta (60 microg/kg, i.p.) induced the phosphorylation of ERK1/2 in areas at the interface between brain and blood or cerebrospinal fluid: meninges, circumventricular organs, endothelial like cells of the blood vessels, and in brain nuclei involved in behavioral depression, fever and neuroendocrine activation: paraventricular nucleus of the hypothalamus, supraoptic nucleus, central amygdala and arcuate nucleus. Double labeling of phosphorylated ERK1/2 and cell markers revealed the expression of phosphorylated ERK1/2 in neurons, astrocytes and microglia. Since phosphorylated ERK1/2 was found in structures in which type I IL-1 receptor has already been identified as well as in structures lacking this receptor, activation of ERK1/2 is likely to occur in response to both direct and indirect action of interleukin-1beta on its target cells.

Animals↗
PubMed2002

Proteomic analysis of human brain identifies alpha-enolase as a novel autoantigen in Hashimoto's encephalopathy.

Hashimoto's encephalopathy (HE) is a rare autoimmune disease associated with Hashimoto's thyroiditis (HT). To identify the HE-related autoantigens, we developed a human brain proteome map using two-dimensional electrophoresis and applied it to the immuno-screening of brain proteins that react with autoantibodies in HE patients. After sequential MALDI-TOF-MASS analysis, immuno-positive spots of 48 kDa (pI 7.3-7.8) detected from HE patient sera were identified as a novel autoimmuno-antigen, alpha-enolase, harboring several modifications. Specific high reactivities against human alpha-enolase were significant in HE patients with excellent corticosteroid sensitivity, whereas the patients with fair or poor sensitivity to the corticosteroid treatment showed less reactivities than cut-off level. Although a few HT patients showed faint reactions to alpha-enolase, 95% of HT patients, patients with other neurological disorders, and healthy subjects tested were all negative. These results suggest that the detection of anti-alpha-enolase antibody is useful for defining HE-related pathology, and this proteomic strategy is a powerful method for identifying autoantigens of various central nervous system diseases with unknown autoimmune etiologies.

Amino Acid Sequence↗
PubMed2000

Adeno-associated virus mediated gene transfer into primary rat brain neuronal and glial cultures: enhancement with the pH-sensitive surfactant dodecyl 2-(1'-imidazolyl) propionate.

This study evaluated the effects of a novel, pH-sensitive surfactant, dodecyl 2-(1'-imidazolyl) propionate (DIP), on cationic lipid mediated transfection in primary rat brain neuronal and glial cultures. The cationic lipid complex DOTAP/DOPE (1, 2-dioleoyl-3-trimethylammonium propionate and dioleoyl phosphatidylethanolamine, respectively) was added over a range of concentrations (0-120 microg/ml) with DNA concentration kept constant (1.6 microg/ml). The neuron-specific enolase (NSE) and cytomegalovirus (CMV) promoters were found to drive green fluorescent protein (GFP) expression in neuron-enriched and glial cultures, respectively, using adeno-associated virus (AAV) derived constructs. NSE-driven GFP expression was not observed in glial cultures. Addition of DOTAP/DOPE increased transfection efficiency over a wide range of lipid concentrations (5-50 microg/ml) keeping DNA concentration constant (1.6 microg/ml). Addition of DIP to the lipid/DNA complex increased maximum transfection efficiencies in glial and neuronal cultures 2-3-fold. Transfection efficiencies were at their maximum with a similar total lipid concentration (50 microg/ml) in both cell-types in the presence of DIP. Neuronal cultures were more sensitive than glia to the toxic actions of DOTAP/DOPE, with or without DIP. These results indicate that AAV-mediated gene-transfer to neurons and glia can be facilitated by addition of a pH-sensitive surfactant to cationic liposome/DNA complexes and that endosomal escape could be a limiting factor in transgene expression.

Animals↗
PubMed2001

Increase of Candida cell virulence by anticancer drugs and irradiation.

The influence of anticancer drugs and irradiation on Candida cell proliferation, adherence to HeLa cells and susceptibility to antifungal drugs (amphotericin B and miconazole) and neutrophils were examined using two Candida albicans strains. After treatment with 5-fluorouracil (25 microg/ml to 250 microg/ml), cis-diammine-dichloroplatinum (10 microg/ml to 100 microg/ml), peplomycin (0.5 microg/ml to 5 microg/ml) or 137Cs (20 Gy to 40 Gy) for 3 days or more, surviving Candida cells proliferated more rapidly than did untreated control cells. Anticancer agent-pretreated Candida cells revealed an increased adhesion to HeLa cells corresponding to an increase of binding to the lectins. The concentration of half limited colony formation (IC50) of amphotericin B and miconazole was increased to near two-fold that of the control by pretreatment of Candida cells with the anticancer agents, except peplomycin, which only weakly increased IC50. In addition, the enolase and Candida acid proteinase activities in the culture supernatants were increased by pretreatment with the drugs and irradiation. Correspondingly, surviving Candida cells after these treatments were resistant to neutrophils, with a reduction to half of the killing. These results indicate that anti-cancer drugs and irradiation potentiate the virulence of Candida cells, or they eliminate Candida cells with low virulence, thereby enhancing the risk of oral and systemic candidiasis.

Amphotericin B↗
PubMed1992

Taxon-specific recruitment of enzymes as major soluble proteins in the corneal epithelium of three mammals, chicken, and squid.

Studies of others have shown that class 3 aldehyde dehydrogenase is a major component of the epithelial cells of the mammalian cornea. Here we demonstrate by peptide sequencing that other major proteins of the corneal epithelium are also identical or related to enzymes in the human, mouse, kangaroo, chicken, and squid. Aldehyde dehydrogenase class 3 was found to be the major protein of human, mouse, and kangaroo corneal epithelial cells. Peptidyl prolyl cis-trans isomerase (cyclophilin) or a homologue thereof is strikingly abundant in the corneal epithelial cells of chicken, but not mammals, and appears to be absent from the cornea of squid. By contrast, enolase or its homologue is relatively abundant in both the mammalian and chicken corneal epithelial cells. In some instances, abundant enzymes are common to cornea and lens in the same species--for example, arginino-succinate lyase/delta 1-crystallin in the chicken and glutathione S-transferase-like protein in the squid; in other cases, the abundant proteins in the cornea have not been found as lens crystallins in any species--for example, aldehyde dehydrogenase class 3 and cyclophilin. These data suggest that enzymes and certain enzyme-crystallins have been recruited as major corneal proteins in a taxon-specific manner and may serve structural rather than, or as well as, enzymatic roles in corneal epithelial cells.

Amino Acid Sequence↗
PubMed2004

Transgenic mouse model of early-onset DYT1 dystonia.

Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice, although levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.

Amino Acid Sequence↗
PubMed2004

A novel role for polyamines in adult neurogenesis in rodent brain.

Although neurogenesis in the adult is known to be regulated by various internal cues such as hormones, growth factors and cell-adherence molecules, downstream elements underlying their action at the cellular level still remain unclear. We previously showed in an insect model that polyamines (putrescine, spermidine and spermine) play specific roles in adult brain neurogenesis. Here, we demonstrate their involvement in the regulation of secondary neurogenesis in the rodent brain. Using neurosphere assays, we show that putrescine addition stimulates neural progenitor proliferation. Furthermore, in vivo depletion of putrescine by specific and irreversible inhibition of ornithine decarboxylase, the first key enzyme of the polyamine synthesis pathway, induces a consistent decrease in neural progenitor cell proliferation in the two neurogenic areas, the dentate gyrus and the subventricular zone. The present study reveals common mechanisms underlying birth of new neurons in vertebrate and invertebrate species.

Animals↗
PubMed2004

Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons.

The N-methyl-D-aspartate receptor (NMDAR) contributes to central sensitization in the spinal cord and the generation of pain hypersensitivity. NMDAR function is modulated by post-translational modifications including phosphorylation, and this is proposed to underlie its involvement in the production of pain hypersensitivity in the spinal cord. We now show that a noxious heat stimulus applied to the rat hindpaw induces phosphorylation of the NMDAR NR1 subunit at a protein kinase C (PKC)-dependent site, serine-896, in superficial dorsal horn neurons. Phosphorylation of NR1 serine-896 is essentially absent in the superficial dorsal horn laminae of naïve rats, but there is rapid (< 2 min) induction following a noxious but not innocuous heat stimulus. The number of pNR1-immunoreactive neuronal profiles in the superficial dorsal horn peaks 30 min after noxious heat stimulation and persists for up to 1 h. pNR1serine896 induction occurs in the endoplasmic reticulum, suggesting that it contributes to trafficking of the receptor from intracellular stores to the membrane. The phosphorylation of the subunit is attenuated by intrathecal injection of the NMDAR antagonist, MK801, suggesting that the NMDAR is involved via a feed-forward mechanism in its own phosphorylation. The pNR1serine896-positive neurons are highly co-localized with PKCdelta and only rarely with PKCgamma. These data provide evidence for an activity-dependent NMDAR phosphorylation at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons initiated by peripheral noxious stimuli.

Animals↗
PubMed2005

Doublecortin expression levels in adult brain reflect neurogenesis.

Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions.

Animals↗