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Biomedical subjects

M E Charness

Publications and source records attributed to M E Charness.

At least 37 records · Page 2Linked to original sources
PubMed1994

Ethanol inhibits neural cell-cell adhesion.

Gestational exposure to ethanol causes defects in neuronal migration, fasciculation, and synaptogenesis, developmental events that depend on the patterned expression and function of cell adhesion molecules (CAMs). Recombinant human osteogenic protein-1 (hOP-1) increases cell-cell adhesion and promotes cell clustering in proliferating neuroblastoma x glioma hybrid NG108-15 cells by strongly inducing N-CAM and L1. Here we show that concentrations of ethanol achieved during social drinking inhibit hOP-1-induced cell clustering without affecting cell proliferation, the induction and cell surface expression of N-CAM and L1, or the alternative splicing and sialylation of N-CAM. This inhibition was reproduced by other alcohols in proportion to their chain length, but not by teratogenic anticonvulsants or phenylalanine. Ethanol inhibition of hOP-1 morphogenesis was inversely proportional to the concentration of hOP-1 and, hence, to the levels of N-CAM and L1. Low concentrations of ethanol (IC50 5-10 mM) inhibited cell-cell adhesion in hOP-1-treated cells, and this action too was reproduced more potently by propanol and butanol. Ethanol may perturb brain and skeletal development by inhibiting CAM-mediated cell-cell interactions.

Antigens, Surface↗
PubMed1994

Regulation of neural cell adhesion molecule and L1 by the transforming growth factor-beta superfamily. Selective effects of the bone morphogenetic proteins.

The transforming growth factor-beta (TGF-beta) superfamily plays a role in embryogenesis and regeneration. We have reported that osteogenic protein-1 (OP-1) promotes cell aggregation and induces the expression of the neural cell adhesion molecules N-CAM and L1 in proliferating neuroblastoma x glioma hybrid NG108-15 cells (Perides, G., Safran, R. M., Rueger, D. C., and Charness, M. E. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 10326-10330; Perides, G., Hu, G., Rueger, D. C., and Charness, M. E. (1993) J. Biol. Chem. 268, 25197-25205). Here we show that the structurally homologous bone morphogenetic proteins (BMP) BMP-2 and BMP-4 are 10-50-fold more potent in these actions than the subfamily comprising BMP-5, BMP-6, and OP-1 (BMP-7). In contrast, members of the TGF-beta subfamily, activin-A, inhibin-A, and 29 additional growth factors and cytokines did not induce N-CAM. The addition of serum to cells growing in serum-free medium caused a concentration-dependent increase in N-CAM and L1 expression; however, serum did not potentiate the induction of N-CAM and L1 by 40 ng/ml OP-1. These findings suggest the presence in NG108-15 cells of a BMP-2/BMP-4 receptor that discriminates subtle differences in structure among homologous members of the TGF-beta superfamily. An endogenous ligand for this receptor may be present in serum.

Animals↗
PubMed1994

Limb dystonia following electrical injury.

Electrical injuries of the extremities may cause paralysis, muscle atrophy, sensory deficit, causalgia, and reflex sympathetic dystrophy (RSD). Limb dystonia has rarely been reported following electrical injury to an extremity, although it may result from cerebral hemisphere electrical trauma. Following electrical injury to the upper extremity, three patients developed limb dystonia accompanied by severe pain and sensory symptoms in two patients and features of RSD in one patient. Two patients received botulinum toxin injections without functional benefit. The mechanism of dystonia following peripheral trauma is unknown but may relate to reorganization of central synaptic connections, possibly in the spinal cord.

Adult↗
PubMed1993

Osteogenic protein-1 regulates L1 and neural cell adhesion molecule gene expression in neural cells.

Osteogenic protein-1 (OP-1) is a member of the TGF-beta superfamily that is expressed in the nervous system. We recently showed that human recombinant osteogenic protein-1 (hOP-1) strongly promotes the aggregation of dividing neuroblastoma x glioma hybrid NG108-15 cells, in part by inducing the major isoforms of the neural cell adhesion molecule (N-CAM) (Perides, G., Safran, R. M., Rueger, D. C., and Charness, M. E. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 10326-10330). Here we show that hOP-1 induces L1 expression approximately 6-fold in NG108-15 cells without changing the levels of N-cadherin, neurofilament 200, Thy-1, tau, and G alpha s. OP-1 induction of L1 and N-CAM was unassociated with changes in cell proliferation and was not reproduced by cellular differentiation. The increased adhesiveness of hOP-1-treated NG108-15 cells could be inhibited in part by Fab fragments of an anti-L1 polyclonal antiserum. L1 and N-CAM expression first increased 12-18 h after hOP-1 treatment, reached a maximum after 2-3 days, persisted for up to 5 days, and returned to control levels 3 days after hOP-1 withdrawal. The increases in L1 and N-CAM protein levels were preceded or accompanied by large increases in the abundance of L1 and all detectable N-CAM mRNAs. Actinomycin D prevented the induction by hOP-1 of L1 and N-CAM mRNAs, suggesting that hOP-1 regulates immunoglobulin CAM gene transcription. OP-1 is the first described growth factor that regulates both N-CAM and L1 gene expression.

Bone Morphogenetic Protein 7↗
PubMed1993

Ethanol differentially increases alpha 2-adrenergic and muscarinic acetylcholine receptor gene expression in NG108-15 cells.

Modulation of alpha 2-adrenergic and opioid neurotransmission may contribute to ethanol intoxication, tolerance, and physical dependence. We showed previously that ethanol increased the expression of functional delta-opioid receptors in NG108-15 cells (Charness, M. E., Querimit, L. A., and Diamond, I. (1986) J. Biol. Chem. 261, 3164-3169). Here we report that long-term (2 days) treatment of NG108-15 cells with ethanol increased the binding of the alpha 2-adrenergic receptor (alpha 2AR) antagonist [3H]rauwolscine and the muscarinic acetylcholine receptor (mAChR) antagonist [3H]quinuclidinyl benzilate by 2.8- and 1.4-fold, respectively. Increased receptor expression was associated with a proportionate increase in the potency of oxymetazoline and carbachol in inhibiting cAMP accumulation. Ethanol did not change the expression of G alpha i2 and reduced levels of G alpha s. Pertussis toxin pretreatment did not prevent the ethanol-induced increase in alpha 2AR, mAChR, and delta-opioid receptor expression. Ethanol caused a large (3.6-fold), dose-dependent increase in the abundance of alpha 2BAR mRNA (rat cDNA probe RNG, 4.1-kb transcript). Ethanol-induced increases in alpha 2BAR and alpha 2CAR (rat probe RG10, 2.5-kb transcript) mRNAs were first detected after 6 h of exposure to 100 mM ethanol, became maximal after 24 h, and persisted for up to 5 days. In contrast, ethanol caused only a small (1.3-fold) increase in the abundance of hm4 mAChR mRNA and did not change levels of G alpha i2 and G alpha s mRNAs. Our data indicate that clinically attainable concentrations of ethanol regulate alpha 2AR gene expression within the time frame of a single session of drinking.

Animals↗
PubMed1993

Brain lesions in alcoholics.

Brain lesions in alcoholics are multifactorial in origin. Ethanol neurotoxicity, Wernicke's encephalopathy, hepatocerebral degeneration, head trauma, central pontine myelinolysis, Marchiafava-Bignami syndrome, pellagra, and premorbid pathological conditions, such as fetal alcohol syndrome, may all contribute to cognitive dysfunction in alcoholics. With the exception of ethanol neurotoxicity, all of these conditions are associated with specific neuropathological lesions. Wernicke's encephalopathy, the neurological syndrome of thiamine deficiency, is frequently overlooked during life and may cause global dementia as well as the more familiar Korsakoff's amnestic syndrome. Distinguishing ethanol neurotoxicity from nutritional deficiency can be facilitated by magnetic resonance imaging, which can visualize some of the specific macroscopic lesions of Wernicke's encephalopathy, central pontine myelinolysis, cerebellar degeneration, and Marchiafava-Bignami syndrome. Computerized morphometric studies of alcoholic brains have revealed ventricular enlargement, selective loss of subcortical white matter, and alterations in neuronal size, number, architecture, and synaptic complexity. These lesions tend to be more severe when there is coexisting nutritional deficiency or liver disease, suggesting that ethanol neurotoxicity may not be the sole cause. A search for similar lesions in nonalcoholic Wernicke's encephalopathy and nonalcoholic liver disease will help determine the specificity of these lesions.

Alcohol Amnestic Disorder↗
PubMed1993

Ethanol increases delta-opioid receptor gene expression in neuronal cell lines.

Long-term treatment with ethanol increases delta-opioid receptor (DOR) expression in the NG108-15 neuroblastoma x glioma hybrid cell line. To determine the underlying mechanism, we studied the effects of ethanol on [3H]diprenorphine binding to intact cells and DOR gene expression in four related clonal neural cell lines. Incubation with 200 mM ethanol for 48 hr increased [3H]diprenorphine binding by 1.4- (N18TG2), 1.8- (NG108-15), 1.9- (N4TG1), and 3.0-fold (N1E-115). Treatment with 25, 50, or 100 mM ethanol for 1 week caused a dose-dependent increase in receptor expression. Receptor up-regulation was associated with an increase in the potency of etorphine for inhibiting prostaglandin E1-stimulated cAMP accumulation. Constitutive DOR expression differed more than 3-fold among the different cell lines and correlated positively with basal cAMP levels. Long-term ethanol treatment increased basal cAMP levels in three of the four cell lines, but did not induce cellular differentiation. Northern blot analysis demonstrated an identical pattern of multiple transcripts in the four cell lines. Ethanol increased the abundance of DOR mRNA by approximately 3-fold in N18TG2 cells and by approximately 5-fold in the remaining cell lines. These findings indicate that clinically relevant concentrations of ethanol regulate DOR expression by increasing the abundance of DOR mRNA. The disparity between the increase in gene expression and ligand binding suggests that ethanol may also modify mRNA translation or receptor processing.

Animals↗
PubMed1992

Induction of the neural cell adhesion molecule and neuronal aggregation by osteogenic protein 1.

The neural cell adhesion molecule (N-CAM) plays a fundamental role in nervous system development and regeneration, yet the regulation of the expression of N-CAM in different brain regions has remained poorly understood. Osteogenic protein 1 (OP-1) is a member of the transforming growth factor beta superfamily that is expressed in the nervous system. Treatment of the neuroblastoma-glioma hybrid cell line NG108-15 for 1-4 days with recombinant human OP-1 (hOP-1) induced alterations in cell shape, formation of epithelioid sheets, and aggregation of cells into multilayered clusters. Immunofluorescence studies and Western blots demonstrated a striking differential induction of the three N-CAM isoforms in hOP-1-treated cells. hOP-1 caused a 6-fold up-regulation of the 140-kDa N-CAM, the isoform showing the highest constitutive expression, and a 29-fold up-regulation of the 180-kDa isoform. The 120-kDa isoform was not detected in control NG108-15 cells but was readily identified in hOP-1-treated cells. Incubation of NG108-15 cells with an antisense N-CAM oligonucleotide reduced the induction of N-CAM by hOP-1 and decreased the formation of multilayered cell aggregates. Anti-N-CAM monoclonal antibodies also diminished the formation of multilayered cell aggregates by hOP-1 and decreased cell-cell adhesion when hOP-1-treated NG108-15 cells were dispersed and replated. Thus, hOP-1 produces morphologic changes in NG108-15 cells, at least in part, by inducing N-CAM. These observations suggest that OP-1 or a homologue may participate in the regulation of N-CAM during nervous system development and regeneration.

Animals↗
PubMed1991

Unilateral oculomotor palsy and bilateral ptosis from paramedian midbrain infarction.

Lesions of the oculomotor fascicles are localized clinically by associated neurologic deficits. We present two patients with bilateral ptosis, unilateral paresis of all other muscles innervated by the oculomotor nerve, and sparing of the contralateral superior rectus muscle--findings suggesting a lesion of the proximal oculomotor fascicles and the central caudal subnucleus. To our knowledge, these are the first such cases with radiologic confirmation of a lesion within the dorsal, paramedian midbrain.

Adult↗
PubMed1989

Ethanol and opioid receptor signalling.

Ethanol may modulate endogenous opioid systems by disrupting opioid receptor signalling. Low concentrations of ethanol slightly potentiate mu-opioid receptor binding by increasing receptor Bmax, and, in some cases, chronic ethanol exposure decreases the density or affinity of the mu-opioid receptors. By contrast, high concentrations of ethanol acutely decrease delta-opioid receptor binding by decreasing receptor affinity, whereas chronic exposure of animals and neuronal cell lines to lower concentrations of ethanol leads to possibly adaptive increases in the density or affinity of the delta-opioid receptors. In the neuronal cell line NG108-15, ethanol does not up-regulate the delta-opioid receptor by blocking receptor degradation or endocytosis, but protein synthesis is required for this response. Up-regulation of the delta-opioid receptor renders ethanol-treated NG108-15 cells 3.5-fold more sensitive to opioid inhibition of adenylyl cyclase. Long-term treatment with ethanol also increases maximal opioid inhibition in NG108-15 cells, possibly by decreasing levels of G alpha s and its mRNA. Ethanol differentially modulates signal transduction proteins in three additional neuronal cell lines, N18TG2, N4TG1, and N1E-115. Ethanol-treated N18TG2 cells show the least up-regulation of the delta-opioid receptor, little heterologous desensitization of adenylyl cyclase, and no changes in G alpha s or G alpha i. By contrast, ethanol-treated N1E-115 cells show the largest up-regulation of the delta-opioid receptor, the most heterologous desensitization of adenylyl cyclase, and concentration-dependent decreases in G alpha s and increases in G alpha i. Further analysis of these related neuronal cell lines may help to identify the molecular elements that endow some, but not all, neuronal cells with the capacity to adapt to ethanol.

Animals↗
PubMed1988

Ethanol differentially regulates G proteins in neural cells.

Long-term incubation of clonal neural cell lines with ethanol differentially reduces the stimulation of cAMP accumulation by hormones and cholera toxin. In the NG108-15 neuroblastoma chi glioma hybrid cell line, this heterologous desensitization was associated with a 42% reduction in the expression of Gs alpha and no significant change in Gi alpha. By contrast, ethanol treatment of the parental neuroblastoma cell line N18TG2 caused little loss of response to hormones or cholera toxin and no significant change in Gs alpha or Gi alpha. Ethanol induced heterologous desensitization in N1E-115 neuroblastoma cells; however, this cell line showed a dose-dependent increase in Gi alpha and a later decrease in Gs alpha. Thus, ethanol causes heterologous desensitization of hormone-stimulated cAMP accumulation by different mechanisms in related neural cell lines.

Alprostadil↗
PubMed1987

Mamillary body atrophy in Wernicke's encephalopathy: antemortem identification using magnetic resonance imaging.

We used magnetic resonance imaging to determine the volume of the mamillary bodies in 9 patients with chronic Wernicke's encephalopathy, 7 patients with presumed Alzheimer's disease, and 37 control patients. The mean mamillary body volume (+/- standard error) was 21.3 +/- 5.8 mm3 in Wernicke patients, 40.1 +/- 3.7 mm3 in Alzheimer patients, and 51.7 +/- 2.5 mm3 in control patients. Seven of nine (78%) patients with chronic Wernicke's encephalopathy had smaller mamillary bodies than 36 of 37 control patients and 7 of 7 Alzheimer patients. The decrease in mamillary body volume was related neither to patient age nor to degree of ventricular enlargement, and most likely reflects the mamillary body atrophy that is grossly apparent at autopsy in up to 81% of Wernicke patients. This technique provides a means of identifying the most specific macroscopic lesion of chronic Wernicke's encephalopathy.

Adult↗
PubMed1986

Ethanol increases the expression of functional delta-opioid receptors in neuroblastoma x glioma NG108-15 hybrid cells.

Ethanol inhibits opioid peptide binding to the delta-opioid receptor. When neuroblastoma x glioma NG108-15 hybrid cells are grown with 25-200 mM ethanol, opioid receptor density increases up to 2-fold without a change in receptor affinity. Since changes in neurotransmitter receptor density may be important in neuronal adaptations to ethanol, we investigated the underlying mechanisms and functional consequences of this phenomenon. The opiate antagonist, naloxone, also increased opioid receptor number, but produced a smaller effect than ethanol with greater fractional inhibition of binding; long term enhancement of binding by ethanol is therefore not a simple function of acute receptor inhibition. Ethanol did not inhibit receptor down-regulation by etorphine, an opiate agonist, and therefore is not likely to increase receptor expression through interference with tonic down-regulation by endogenous opioid peptides. Ethanol increased opioid receptor expression in NG108-15 cells treated with actinomycin D, but not cycloheximide; hence, normal protein synthesis, but not DNA transcription, may be required for this response. The opioid receptors induced in ethanol-treated cells were subject to normal up-regulation by naloxone, down-regulation by etorphine, and acute inhibition of agonist binding by Na+. Etorphine maximally inhibits cyclic AMP accumulation in NG108-15 cells with only fractional occupancy of opioid receptors. Chronic ethanol exposure increased the receptor reserve for this response, resulting in a 3.5-fold increase in the potency of etorphine for inhibiting phenylisopropyladenosine-stimulated cyclic AMP accumulation. Neuronal adaptation to ethanol may involve changes in the density of receptors that regulate cellular levels of cyclic AMP.

Cell Line↗