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Biomedical subjects

E Appel

Publications and source records attributed to E Appel.

At least 19 recordsLinked to original sources
PubMed2001

Macrophages express neurotrophins and neurotrophin receptors. Regulation of nitric oxide production by NT-3.

In this study we examined the expression of neurotrophins and their receptors in mouse macrophages and the effects of the neurotrophins on nitric oxide secretion. Macrophages expressed TrkB and TrkC but not BDNF, NT-3 or NT-4. LPS induced up-regulation of TrkB and TrkC and of BDNF and NT-3 expression. Treatment of macrophages with NT-3 increased the secretion of nitric oxide in LPS-treated macrophages and this increase was blocked by K252a, a Trk kinase inhibitor. In contrast, BDNF and NT-4 had no significant effects on the induction of nitric oxide. Our results suggest that NT-3 play important roles in the function of macrophages during inflammatory responses and in tissue repair.

Animals↗
PubMed2001

vFLIP protects PC-12 cells from apoptosis induced by Sindbis virus: implications for the role of TNF-alpha.

Sindbis virus (SV) is an alphavirus used as a model for studying the pathogenesis of viral encephalitis. In this study we examined the effects and the mechanisms involved in the apoptosis induced by SV in PC-12 cells, and the role of a vFLIP in this process. Infection of PC-12 cells with a neurovirulent strain of SV, SVNI, induced cell apoptosis. Overexpression of vFLIP encoded by the HHV-8 or treatment with a caspase-8 inhibitor inhibited cell apoptosis. SVNI induced an increase in the expression of tumor necrosis factor alpha (TNF-alpha), and pre-treatment of the cells with an anti-TNF-alpha blocking antibody or with soluble TNF-alpha receptor abrogated the apoptotic effect of SVNI. Moreover, TNF-alpha R1 knockout mice were more resistant to the cytopathic effects of the virus as compared to control animals. Our results indicate that the apoptosis induced by SVNI is mediated by activation of caspase-8, and that TNF-alpha plays an important role in the apoptotic response.

Animals↗
PubMed2001

Roles of BCL-2 and caspase 3 in the adenosine A3 receptor-induced apoptosis.

Selective A3 adenosine receptor agonists have been shown to induce apoptosis in a variety of cell types. In this study we examined the effects of adenosine receptor agonists selective for A1, A2A, or A3 receptors on the induction of apoptosis in primary cultures of rat astrocytes and in C6 glial cells. Treatment of the cells with the A3 receptor agonist Cl-IB-MECA (10 microM) induced apoptosis in both cell types. The effects of Cl-IB-MECA were partially antagonized by the A3 receptor-selective antagonist MRS 1191. In contrast, the A1 and A2A receptor agonists, CPA and CGS 21680, respectively, did not have significant effects on apoptosis in these cells. Cl-IB-MECA reduced the expression of endogenous Bcl-2, whereas it did not affect the expression of Bax. Overexpression of Bcl-2 in C6 cells abrogated the induction of apoptosis induced by the A3 agonist. Cl-IB-MECA also induced an increase in caspase 3 activity and caspase inhibitors decreased the apoptosis induced by the A3 agonist. These findings suggest that intense activation of the A3 receptor is pro-apoptotic in glial cells via bcl2 and caspase-3 dependent pathways.

Adenosine↗
PubMed2001

Nerve growth factor regulates TNF-alpha production in mouse macrophages via MAP kinase activation.

In this study, we examined the expression of nerve growth factor (NGF) and its receptors in mouse macrophages and the mechanisms involved in the effect of NGF on tumor necrosis factor (TNF)-alpha production. Macrophages expressed NGF and the NGF receptors TrkA and p75. Treatment of J744 cells or peritoneal macrophages with NGF induced a large increase in the production of TNF-alpha. In addition, NGF induced the secretion of nitric oxide in interferon-gamma-treated J774 cells or lipopolysaccharide-treated peritoneal macrophages. The induction of TNF-alpha production by NGF was blocked by K252a, an inhibitor of the TrkA receptor. NGF induced phosphorylation and activation of extracellular signal-regulated kinase, Erk1/Erk2 and c-Jun amino-terminal kinase, whereas it did not induce phosphorylation of p38 mitogen-activated protein kinase. Inhibition of the MAP kinase-Erk kinase pathway with PD 098059 decreased the secretion of TNF-alpha by NGF. Our results suggest that NGF has an important role in the activation of macrophages during inflammatory responses via activation of mitogen-activated protein kinases.

Animals↗
PubMed2000

Differential regulation of Bcl-2 and Bax expression in cells infected with virulent and nonvirulent strains of sindbis virus.

Sindbis virus is an alphavirus that infects cells in either lytic or persistent infection. In this study we examined the effects of Sindbis virus on cell apoptosis and on the expression of Bcl-2 and Bax. Of the two strains studied, SVA and SVNI, only the neurovirulent strain, SVNI, induced apoptosis of astrocytes and PC-12 cells. SVA, which infects cells in a persistent manner, induced up-regulation of bcl-2 mRNA and Bcl-2 protein, whereas SVNI induced an increase in Bax levels. Our results indicate a differential regulation of Bcl2 and Bax expression by SVA and SVNI, which may be associated with the apoptotic potential of the viruses.

Animals↗
PubMed2000

Differential regulation of neurotrophin expression by mitogens and neurotransmitters in mouse lymphocytes.

In this study, we examined the expression of neurotrophins in mouse lymphocytes and the regulation of their expression by mitogens and neurotransmitters. We found that mixed splenocytes as well as T and B lymphocytes expressed mRNA for all the neurotrophins examined. Differential regulation of the neurotrophins was obtained upon stimulation of the cells. Thus, LPS increased the expression of NGF, BDNF and NT-3 in splenocytes and B cells, whereas Con-A increased the mRNA of NT-3 and NT-4 in T cells and NGF expression in splenocytes. The neurotransmitter substance P and the beta-adrenergic agonist, isoproterenol induced an increase in the expression of NGF. Our results suggest an important role for the different neurotrophins in the function of the immune system and point to a bi-directional interaction between neurotrophins and neurotransmitters in this system.

Animals↗
PubMed1998

Role of nerve growth factor in a mouse model of allergic airway inflammation and asthma.

The role of nerve growth factor (NGF), a potent mediator acting in the development and differentiation of both neuronal and immune cells, was examined in a mouse model of allergic asthma. NGF-positive cells were detected in the inflammatory infiltrate of the lung and enhanced levels of NGF were detected in serum and broncho-alveolar lavage fluids. Mononuclear cells in inflamed airway mucosa as well as broncho-alveolar macrophages were identified as one source of NGF production. Splenic mononuclear cells from allergen-sensitized mice produced NGF in response to allergen. They responded to exogenously added NGF with a dose-dependent increase in IL-4 and IL-5 production and augmented IgE and IgG1 synthesis. In contrast, IFN-gamma and IgG2alpha levels remained unaffected. The effects were NGF specific, since they could be blocked by an anti-NGF-antibody. Nasal application of anti-NGF to allergen-sensitized mice significantly reduced IL-4 and prevented development of airway hyperreactivity. These results show that allergic airway inflammation is accompanied by enhanced local NGF production that acts as an amplifier for Th2 effector functions and plays an important role in the development of airway hyperreactivity. Therefore it is suggested that NGF may serve as a link between the immune and nerve system.

Allergens↗
PubMed1997

Regulation of GDNF expression in cultured astrocytes by inflammatory stimuli.

Astrocytes express increased levels of neurotrophic factors in response to pathological conditions in the CNS such as injury and inflammation. We have examined the effects of lipopolysaccharide (LPS) and inflammatory cytokines on the expression of GDNF by mouse astrocytes and by C6 glial cells. LPS and tumor necrosis factor-alpha (TNF-alpha) induced an increase in level of glial-derived neurotrophic factor (GDNF) mRNA in both cell types. Similarly, the synthesis of GDNF protein was increased by both treatments. Interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) induced similar effects on GDNF production, whereas IL-2 and IL-6 had no significant effects. These results indicate that the expression of GDNF in astrocytes is regulated by inflammatory stimuli and therefore may provide neurotrophic support to injured neurons in inflammatory conditions in the CNS.

Animals↗
PubMed1995

Improved PCR amplification/Hhal restriction for unambiguous determination of apolipoprotein E alleles.

We present a modification to the polymerase chain reaction amplification/Hhal restriction isotyping method for human apolipoprotein (apo) E. This method includes a mutagenic forward primer and 5'-end labeling of both primers. These modifications of the original method described by Hixon and Vernier (J Lipid Res 1990;31:545-8) allow sensitive and unambiguous determination of apoE genotypes.

Alleles↗
PubMed1982

Sympathomimetic effects of amezinium on the cardiovascular system and plasma catecholamines in man.

The cardiovascular effects of the sympathomimetic agent amezinium were investigated in a double-blind, placebo-controlled, randomized trial in six volunteers. Before and 2 h after oral administration of amezinium 30 mg or placebo the cardiovascular responses to orthostatic stress, induced by 80 degrees passive head-up tilt, were assessed by recording blood pressure, systolic time intervals, and echocardiogram. Plasma catecholamines were also determined. After amezinium treatment, the average supine systolic blood pressure was increased by +30 mm Hg and after tilting it remained above both the pre-treatment and placebo values. Compared to placebo, amezinium elicited only minor changes in heart rate and diastolic blood pressure. The effect of amezinium on the pre-ejection period corrected for heart rate (PEPc) and mean velocity of fiber shortening (VCFmean) indicated positive inotropic properties. Its effects were distinctly more pronounced during tilt than with the subjects supine. Plasma concentrations of noradrenaline and adrenaline were not influenced by amezinium during rest or tilt. From these results and previous research it is concluded that amezinium induces its sympathomimetic effects by preferentially inhibiting the re-uptake of noradrenaline which is released by the drug itself, or by sympathetic activation during tilt. This mechanism of action might explain the pronounced sympathomimetic effects of the drug, especially during orthostatic stress.

Adult↗
PubMed1981

Determination of plasma catecholamines by means of radioenzymatic labelling and high pressure liquid chromatographic separation.

0.05 ml plasma samples are incubated with 3H-S-adenosylmethionine and catechol-O-methyl-transferase. The resulting methodoxy derivatives are extracted, the extracts separated by high pressure liquid chromatography and the metanephrine fractions collected. Evaluation is performed by liquid scintillation counting of radioactivity in the respective fractions. The following performance criteria are presented: precision, accuracy, detectability (40 pg/ml for adrenaline and noradrenaline, 130 pg/ml for dopamine), linearity and day-by-day variation. Comparison with a standard method shows an excellent correlation for adrenaline and noradrenaline.

Adult↗
PubMed1980

Exercise induced changes of catecholamines and potassium in plasma of dogs after treatment with propranolol.

Previous studies in man have shown that during beta-adrenoceptor blockade physical exercise caused a significantly greater elevation of plasma catecholamines than without blockade. After blockade of beta-adrenoceptors, increased levels of circulating catecholamines should have an unopposed effect on adrenergic alpha-receptors. In order to elucidate such an effect, experiments were performed with 7 trained dogs before and after acute beta-adrenoceptor blockade (0.1 mg/kg (-)-propranolol i. v.). Exercise was performed on a conveyor (10 min, 10 km/h, slope 10%). Besides catecholamine concentrations in plasma, as an index of alpha-receptor-stimulation potassium concentrations in plasma were determined. Immediately after exercise, plasma noradrenaline was increased from 310 to 579 pg/ml, plasma adrenaline from 136 to 222 pg/ml and plasma potassium from 4.23 to 4.6 mmol/l. After beta-adrenoceptor blockade exercise caused a significantly higher increase in plasma noradrenaline from 352 to 755 pg/ml and plasma adrenaline from 172 to 260 pg/ml. Also plasma potassium concentrations were significantly elevated from 4.03 to 5.05 mmol/l. The results indicate an enhanced reflex activation of sympatho-neuronal and sympatho-adrenal mechanisms during exercise after beta-adrenoceptor blockade; the increased concentrations of noradrenaline at the adrenoceptors might reduce the efficiency of beta-blockade. Concomitantly, increased stimulation of alpha-adrenoceptors is elicited, which becomes obvious by an increase of potassium concentration in plasma.

Animals↗
PubMed1979

Standardized mental stress in healthy volunteers induced by delayed auditory feedback (DAF).

Using delayed auditory feedback (delay 0.175 s) a standardized form of mental stress was investigated in 8 healthy male volunteers. After a resting period and a period of undelayed reading, the volunteers were exposed for 5 min to the DAF stress. During the DAF period heart rate increased by 10% and systolic and diastolic blood pressure increased by 9% and 18%, respectively. As a measure of acute sympathetic activation, plasma concentrations of norepinephrine and epinephrine rose by 68% and 49%, respectively. The activity od dopamine-beta-hydroxylase in plasma was increased by 25%. From these results it can be concluded that the DAF procedure provides a suitable method for inducing a standardized mental stress in normal subjects, which can be measured as changes in biochemical and cardiovascular variables.

Acoustic Stimulation↗
PubMed1979

Sympathoneuronal and sympathoadrenal activation during ketamine anesthesia.

The effects of ketamine anesthesia (3 mg/kg i.v.) on cardiovascular parameters and noradrenaline, adrenaline and dopamine-beta-hydroxylase (DBH) activity in plasma were studied in 12 patients. At 3, 6 and 10 min after induction of anesthesia, a pronounced increase in heart rate (+28%) and in systolic and diastolic blood pressure (+28% and 17% resp.) was observed. Concomitantly noradrenaline and adrenaline concentrations increased significantly from 187 to 415 ng/l and from 97 to 271 ng/l, respectively. DBH-activity in plasma remained almost unchanged. From these results it can be concluded that the well known cardiovascular stimulant effect of ketamine is due to greatly enhanced sympatho-neuronal and sympatho-adrenal activity, presumably brought about by a central mechanism of action of the drug. Furthermore, DBH-activity in plasma appeared not to be a reliable index of sympathetic activity in man.

Adrenal Glands↗
PubMed1979

[The effect of hypothermia and methoxyflurane-anaesthesia on sympatho-neuronal and sympatho-adrenal activity in the course of cardiac surgery (author's transl)].

The concentrations of adrenaline and noradrenaline, and dopamine-beta-hydroxylase in the plasma, and certain haemodynamic parameters, were determined in 14 children undergoing surgical correction of congenital cardiac defects under hypothermia at 30 degrees C and methoxyflurane anaesthesia. During the pre-operative phase of hypothermia at 30 degrees C, the adrenaline levels rose to about 300% of the inital levels, and the noradrenaline levels to about 200%. During the postoperative phase of re-warming at 34 degrees C, a further dysregulative release of catecholamines led to an increase in adrenaline levels to a critical concentration of about 800% of the norm, and in noradrenaline levels of about 400% of the norm. No change was seen in dopamine-beta-hydroxylase activity. Hypothermia thus results in a massive activation of the sympatho-neuronal and sympatho-adrenal systems, which is not prevented by methoxyflurane anaesthesia, and which may endanger the recently operated heart, particularly during the early post-operative period, because of the increased oxygen requirements imposed on the myocardium. In normothermia, on the other hand, methoxyflurane anaesthesia results in only a slight degree of activation of the sympathetic nervous system, which increased only slightly during the post-operative period. Under these conditions, the plasma dopamine-beta-hydroxylase activity remains unchanged. Unlike the changes in plasma catecholamine levels, dopamine-beta-hydroxylase activity cannot be regarded as an index of changes in sympatho-neuronal activity.

Adolescent↗