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Biomedical subjects

K Lieb

Publications and source records attributed to K Lieb.

51 records · Page 3Linked to original sources
PubMed1996

Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors.

We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A2a-receptor agonist CGS21680 and the non-selective adenosine A1- and A2-receptor agonist 5'-N-ethylcarboxiamidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E2 (PGE2). The adenosine A1-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A1-receptor-specific agonist N6-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine A1-, A2a-, and A3-, but not A2b-receptor mRNAs, whereas astroglial cells expressed adenosine A2b- but not A2a-receptor mRNA. The adenosine A2a-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE2 release. CGS21680-increased PGE2 levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE2. The results strongly suggest that adenosine A2a-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE2. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit.

Adenylyl Cyclase Inhibitors↗
PubMed1996

[Chronic fatigue syndrome. Definition, diagnostic measures and therapeutic possibilities].

This article reviews the chronic fatigue syndrome (CFS), a disorder whose etiology is unknown. The diagnostic criteria proposed in 1994 by the CDC and the International Chronic Fatigue Syndrome Study Group are introduced. In contrast to widespread belief, there are no laboratory tests available to underpin the diagnosis of CFS; the diagnosis is made solely on the basis of clinical criteria. In the differential diagnosis, the exclusion of other conditions that can cause chronic fatigue, such as neuropsychiatric or sleep disorders, is of critical importance. In this context, the question as to whether CFS is a clinical entity that can be differentiated from psychiatric diagnoses, such as depression, somatoform disorder, or neurasthenia, is discussed. At the moment, there is no specific therapy for CFS. Therefore, therapeutic approaches are limited to symptomatic management of the concomitant sleep disturbances, pain, or psychiatric symptoms, such as depression. Patients may benefit from cognitive behavioral therapy, as this may help then to identify and exclude factors contributing to and maintaining chronic fatigue. An integrated medical and psychological approach should be adopted, with the aim of preventing significant secondary negative results of the illness, such as interpersonal conflicts or chronic disability.

Adaptation, Psychological↗
PubMed1996

Effects of substance P and selected other neuropeptides on the synthesis of interleukin-1 beta and interleukin-6 in human monocytes: a re-examination.

Recent studies have suggested that substance P (SP) and some other neuropeptides are able to induce the synthesis of the proinflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6) in peripheral blood mononuclear cells. In the present study, we re-examined these findings by using a completely endotoxin-free monocyte cultivation system. We demonstrate that the neuropeptides SP, vasoactive intestinal peptide, substance K. cholecytokinine, alpha-endorphin and beta-endorphin are consistently unable to induce the synthesis of IL-1 and IL-6 in human peripheral blood monocytes. However, low amounts of LPS (1 pg/ml) synergized with SP to induce IL-6 mRNA expression. In contrast to its lack of effect in monocytes, we were able to confirm the ability of SP to induce cytokine synthesis in astrocytic cells. Our results raise questions about previous results claiming a neuropeptide-induced synthesis of proinflammatory cytokines in human monocytes. In conjunction with other studies, we suggest that undetected levels of endotoxin/LPS in the culture medium may have been primarily responsible for results suggesting an inductive effect of neuropeptides on cytokine synthesis in monocytes.

Blotting, Northern↗
PubMed1996

Interleukin-1 beta uses common and distinct signaling pathways for induction of the interleukin-6 and tumor necrosis factor alpha genes in the human astrocytoma cell line U373.

Cytokines are involved in the etiology of different disorders of the CNS. For a better understanding of their pathogenic role, we analyzed signal transduction pathways mediating the interleukin (IL)-1 beta-induced synthesis of IL-6 and tumor necrosis factor alpha (TNF alpha) in the human astrocytoma cell line U373 MG. Both protein kinase C and reactive oxygen intermediates (ROIs) were involved in IL-6 and TNF alpha gene expression by IL-1 beta. In contrast, protein tyrosine kinases were only necessary for expression of the IL-6 gene. Whereas activation of protein kinase A was able to induce expression of the IL-6 gene, it did not induce TNF alpha gene expression and was not involved in IL-1 beta-induced IL-6 and TNF alpha gene expression. Activation of the transcription factor nuclear factor-kappa B by IL-1 beta involved ROIs, whereas the IL-1 beta-induced activation of the transcription factor AP-1 was mediated via protein kinase C. Our findings provide the basis for the development of specific drugs for the treatment of disorders of the CNS in which cytokines play a pathogenic role.

Astrocytoma↗
PubMed1996

Interleukin-1 beta and tumor necrosis factor-alpha induce expression of alpha 1-antichymotrypsin in human astrocytoma cells by activation of nuclear factor-kappa B.

The protease inhibitor alpha 1-antichymotrypsin (ACT) has been suggested to be involved in the etiology of Alzheimer's disease (AD). Increased levels of ACT have been found in serum and brains of AD patients, and ACT has been proposed to regulate beta-amyloid fibril formation in vitro. To gain insight into the regulation of ACT in the brain, we investigated the signal transduction pathways involved in ACT gene expression and protein synthesis in the human astrocytoma cell line U373. This cell line has previously been shown to respond with strong ACT synthesis on stimulation with interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF alpha). Here, we describe that both IL-1 beta and TNF alpha activate the transcription factor nuclear factor-kappa B (NF-kappa B) via production of reactive oxygen intermediates resulting in ACT expression. In addition, we show that neither protein kinase C nor protein kinase A is involved in IL-1 beta- or TNF alpha-induced ACT expression. These results suggest that activation of NF-kappa B may be one possible cause of increased ACT levels in AD and provide a basis for the development of drugs used for the modulation of inflammatory processes occurring in AD.

Astrocytoma↗
PubMed1996

Sex differentiation of rat hippocampal GABAergic neurons.

In order to analyse mechanisms of sex differentiation of the hippocampus at the cellular level, the differentiation of hippocampal GABAergic neurons was studied in vitro. Serum-supplemented and serum-free dissociated cell cultures were raised from the hippocampus of embryonic day 17 male and female rat embryos for up to 14 days in vitro. This time period roughly corresponds to the critical phase for sex differentiation of the rat brain as determined in vivo. Serum-free cultures were treated with testosterone and/or 17 beta-oestradiol for the entire culture period. Control cultures from male donors contained twice as many GABA-immunoreactive neurons as those from female donors, while there was no sex difference in overall counts of neurons stained for microtubule-associated protein 5. Measurements of high-affinity uptake of [3H]GABA essentially confirmed this sex difference. The development of the sex difference could not be influenced by long-term treatment with androgen or oestrogen. It is concluded that sex differentiation of a specific subpopulation of hippocampal neurons may take place independently of the environment provided by gonadal steroids and in the absence of extrinsic connections with the hypothalamus or other relays of the limbic circuit.

Animals↗
PubMed1995

Stimulation of the sphingomyelin pathway induces interleukin-6 gene expression in human astrocytoma cells.

Interleukin-6 (IL-6) has previously been shown to participate in neurodegenerative processes including Alzheimer's disease. However, the mechanisms leading to increased IL-6 expression in the brain remain largely unknown. We have studied the effects of synthetic ceramides and sphingomyelinase as possible regulators of IL-6 gene expression in a human astrocytoma cell line. The synthetic ceramides C2- and C6-ceramide as well as the enzyme sphingomyelinase were able to induce IL-6 gene transcription and protein synthesis in a dose-dependent manner with maximal IL-6 mRNA levels being reached after 4 h of ceramide treatment. We propose that the sphingomyelin pathway is part of the signal transduction cascade leading to IL-6 gene expression in astrocytes, and that this pathway may be involved in IL-6-mediated neurodegenerative processes.

Astrocytes↗
PubMed1995

IL-1 beta and TNF alpha, but not IL-6, induce alpha 1-antichymotrypsin expression in the human astrocytoma cell line U373 MG.

Cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) have previously been shown to participate in neurodegenerative processes including Alzheimer's disease. However, the molecular consequences of increased cytokine expression in the brain remain largely unknown. We have studied the effects of IL-1, IL-6 and TNF alpha on the expression of the acute-phase protein alpha 1-antichymotrypsin (ACT) in human astrocytoma cell lines. Both IL-1 and TNF alpha, but not IL-6, were able to induce ACT gene transcription and protein synthesis. The synthetic glucocorticoid dexamethasone enhanced cytokine-induced ACT mRNA expression and protein synthesis. We conclude that IL-1-induced expression of ACT may be part of the inflammatory response in the brain and may be involved in the pathology of Alzheimer's disease.

Anti-Inflammatory Agents↗
PubMed1995

Neurotoxicity of dopamine and protective effects of the NMDA receptor antagonist AP-5 differ between male and female dopaminergic neurons.

Neurodevelopmental and neurodegenerative disorders related to dopaminergic transmission typically exhibit a sex-specific prevalence. In order to investigate the underlying cellular mechanisms, primary cultures of dissociated embryonic rat midbrain were subject to a 24 h treatment with dopamine in concentrations between 1 and 1000 microM. Dopamine caused a dose-dependent loss of neurons and reduction of neurites immunoreactive to tyrosine hydroxylase with a LD50 of about 100 microM. Application of D1-like or D2-like receptor agonists instead of dopamine did not induce cell loss. Neither D1-like or D2-like receptor antagonists nor the nitric oxide synthase inhibitor N-nitro-L-arginine were capable of blocking dopamine-induced cell death. When tissue from male and female donors was cultured separately, a twofold sex difference was consistently present: (1) Survival rates of female dopaminergic neurons in the presence of LD50 concentrations of dopamine were about twice those of male neurons. (2) The N-methyl-D-aspartate-receptor antagonist AP-5 was capable of rescuing female but not male dopaminergic neurons from dopamine-induced cell death. It is concluded that dopamine neurotoxicity is not mediated by dopamine receptors and is aggravated by glutamate excitotoxicity but not by nitric oxide. The male-specific vulnerability is the first direct evidence that the prevalence of certain neurodevelopmental or neurodegenerative disorders may have a basis in the biology of the single dopaminergic neuron.

2-Amino-5-phosphonovalerate↗
PubMed1994

Differentiation of hypothalamic GABAergic neurons in vitro: absence of effects of sex and gonadal steroids.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is involved in the control of sexually dimorphic brain functions, such as pituitary secretion and reproductive behavior. Hypothalamic GABAergic systems in vivo exhibit sexually dimorphic functional properties. Sexual dimorphisms in the rat brain are currently thought to be brought about by the organizational influence of gonadal steroids during the perinatal developmental period. The present study is concerned with the question of whether developing hypothalamic GABAergic neurons are primary targets of sex hormones. Since it is impossible to distinguish direct from indirect effects of experimental manipulations of the hormonal environment of the in vivo brain, sex-specific primary cultures raised from embryonic day 14 rat diencephalon and cultured for up to 8 days in vitro (DIV) were used as a model system. Effects of sex steroids were investigated on high affinity uptake of [3H]GABA. GABA transport was already mature at 3 DIV. [3H]GABA uptake was sensitive to inhibition by nipecotic acid and the transmitter was taken up by high affinity transport (Km = 15.2 microM). Immunocytochemical preparations demonstrated extensive networks of GABA-immunoreactive fibers at 8 DIV. Concomitantly with the outgrowth of neurites, there was a marked increase in maximum uptake velocity (Vmax). No differences could be detected regarding cell numbers or uptake kinetics between cultures from male and female donors. Neither cell numbers nor GABA uptake were affected by short- and long-term treatment with estradiol-17 beta or testosterone. It appears that hypothalamic GABAergic neurons in vitro do not develop sex differences in cell numbers or GABA transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Electroencephalographic coherence in acquired immune deficiency syndrome.

We studied a quantitative electroencephalographic (EEG) measure, coherence, in 28 patients with acquired immune deficiency syndrome (AIDS) and 56 uninfected volunteers. Compared with uninfected subjects, AIDS patients had increased coherence in the 6- to 10-Hz band. The largest increases in coherence were between frontal and occipital regions and between temporal and frontal regions. Coherence within contiguous regions was less affected. Eight of the 28 AIDS patients (29%) had clinically abnormal EEG findings, compared with four of the 56 uninfected control subjects (7%). Among the AIDS patients, 12 had normal neuropsychological performance, nine had mild impairment, and six had moderate impairment. Coherence was increased in each subgroup of AIDS patients, including those with normal neuropsychologic performance and/or normal clinical EEG results. AIDS patients were then classified by quantitative EEG power in frontal head regions as "abnormal" (the upper third of patients) or "normal" (the remainder). Increased coherence was found among both groups. Because the development of abnormal neuropsychological performance or a clinically abnormal EEG examination indicates relatively advanced central nervous system disease, alterations in specific coherence measures may detect subclinical effects of the human immunodeficiency virus on brain function before other changes are evident.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Preattentive information processing in schizophrenia.

Preattentive and attentive information processing was investigated in 24 schizophrenic patients and 24 control subjects using a texture discrimination task based on Julesz's texton theory. Texton theory essentially defines a certain limited number of texture elements that can be detected readily and simultaneously without attentional effort irrespective of the size and information content of the rest of the visual field. During the first task, subjects had to detect texton elements (one 'L' among 35 '+'), which were presented on slides for 40 ms and were followed by a mask after different stimulus onset asynchronies (SOA: 200-800 ms). At all SOAs tested schizophrenics reported significantly fewer correct responses compared to the control group. In the second task, subjects had to search for texton (one 'L' among 35 '+') and non-texton elements (one 'L' among 35 'T') in the stimulus displays, whereby response times were measured. Schizophrenics showed significantly slower response times only to texton elements, whereas response times to non-texton elements did not significantly differ from controls. Additionally, schizophrenics made significantly more errors detecting non-texton elements than controls. The results suggest a deficit in processing of visual information in schizophrenic patients, which is confined to preattentive processes and may consist of a slowing of those processes. Schizophrenics may also have difficulty in sustaining their attention during search tasks.

Adult↗
PubMed1990

Differential effects of human and pork insulin-induced hypoglycemia on neuronal functions in humans.

Insulin has been found to cross the blood-brain barrier, and insulin receptors have been detected in different structures of the brain. However, the biological significance of insulin acting in the brain remains unclear. Reports of differential awareness of hypoglycemic symptoms during human insulin (HI)- and pork insulin (PI)-induced hypoglycemia hint at a modulatory influence of insulin on sensory processing. In a double-blind study, we recorded auditory-evoked potentials (AEPs), indexing neuronal transmission along sensory pathways, in 30 healthy male subjects during a baseline condition and HI- and PI-induced mild hypoglycemia of 2.65 mM. Fifteen subjects were tested after 20 min and another 15 after 50 min of constant hypoglycemia. During hypoglycemia, subjects had to indicate the severity of hypoglycemic symptoms and their current mood. Hypoglycemia increased latencies of the P3 component and reduced amplitudes of the N1, P2, and P3 components. Despite identical blood glucose and serum insulin levels in both sessions, effects of PI-induced hypoglycemia on AEP components were significantly stronger than those of HI-induced hypoglycemia (P less than 0.05). Differences between the effects of the insulins were consistently apparent after 20 min of hypoglycemia, indicating a short-term action of these hormones on central nervous system functions. Also, after 20 min, but not after 50 min, of steady-state hypoglycemia, subjects felt more excited during PI than HI infusion (P less than 0.05). The results indicate different influences of HI and PI on sensory function during hypoglycemia. These differences, occurring during early hypoglycemia, could contribute to the differential awareness of hypoglycemic warning symptoms during HI- and PI-induced hypoglycemia in diabetic patients.

Animals↗
PubMedDate not supplied

Interleukin-6-associated inflammatory processes in Alzheimer's disease: new therapeutic options.

The cytokine interleukin-6 is consistently detected in the brains of Alzheimer's disease patients but not in the brains of nondemented elderly persons. Until recently it was unclear whether an interleukin-6-associated inflammatory mechanism is an early or late event in the pathological cascade of Alzheimer's disease. We investigated whether interleukin-6 could be detected in plaques of Alzheimer's disease patients prior to the onset of neuritic degeneration. We found interleukin-6 mostly in plaques where neuritic pathology has not yet developed. This indicates that the appearance of interleukin-6 may precede neuritic changes and is not just a consequence of neuritic degeneration. Therefore, one may hypothesize that activation of inflammatory mechanisms may cause neuritic degeneration in plaques. A suppression of interleukin-6 synthesis could, therefore, be of therapeutic value. Upon screening a number of substances, we found that a small number of nonsteroidal antiinflammatory drugs, including tenidap, were able to inhibit interleukin-6 synthesis in cultured human astrocytoma cells. These substances may be therapeutically useful in Alzheimer's disease and should be evaluated in clinical studies.

Aged↗