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Biomedical subjects

K Lieb

Publications and source records attributed to K Lieb.

At least 37 records · Page 2Linked to original sources
PubMed1999

Borna disease virus in human brains with a rare form of hippocampal degeneration but not in brains of patients with common neuropsychiatric disorders.

To estimate the frequency of persistent Borna disease virus (BDV) infections of the human central nervous system and to determine which neuropsychiatric disorders might be associated with this viral infection, reverse transcription-nested polymerase chain reaction was used to screen a large collection of autopsy brain samples for the presence of BDV-specific nucleic acids. The presence of BDV RNA was found in 3 brains of persons with psychiatric symptoms and prominent hippocampal degeneration previously reported to be positive by others. However, no BDV RNA was detected in 86 randomly collected brains from persons with various psychiatric disorders, including schizophrenia, affective disorders, and Alzheimer's disease, or from suicide victims or in 52 brains from healthy controls. Furthermore, no BDV-RNA was detected in 16 surgical brain samples from persons with epilepsy-associated hippocampal sclerosis. These results indicate that life-long persistent BDV infections are rare in humans and that such infections may be associated with certain forms of hippocampal degeneration.

Adult↗
PubMed1999

Impairment in preattentive visual processing in patients with Parkinson's disease.

We explored the possibility of whether preattentive visual processing is impaired in Parkinson's disease. With this aim, visual discrimination thresholds for orientation texture stimuli were determined in two separate measurement sessions in 16 patients with idiopathic Parkinson's disease. The results were compared with those of 16 control subjects age-matched and 16 young healthy volunteers. Discrimination thresholds were measured in a four-alternative spatial forced-choice paradigm, in which subjects judged the location of a target embedded in a background of distractors. Four different stimulus configurations were employed: (i) a group of vertical targets among horizontal distractors ('vertical line targets'); (ii) targets with varying levels of orientation difference on a background of spatially filtered vertically oriented noise ('Gaussian filtered noise'); (iii) one 'L' among 43 '+' signs ('texton'), all of which assess preattentive visual processing; and (iv) control condition, of one 'L' among 43 'T' distractors ('non-texton' search target), which reflects attentive visual processing. In two of the preattentive tasks (filtered noise and texton), patients with Parkinson's disease required significantly greater orientation differences and longer stimulus durations, respectively. In contrast, their performance in the vertical line target and non-texton search target was comparable to that of the matched control subjects. These differences were more pronounced in the first compared with the second session. Duration of illness and age within the patient group correlated significantly with test performance. In all conditions tested, the young control subjects performed significantly better than the more elderly control group, further indicating an effect of age on this form of visual processing. The results suggest that, in addition to the well documented impairment in retinal processing, idiopathic Parkinson's disease is associated with a deficit in preattentive cortical visual processing.

Adult↗
PubMed1998

[Microglia: mechanisms of activation and significance in pathogenesis of neuropsychiatric illnesses].

Microglia are the resident macrophages of the brain. They are the central cellular element to initiate defense mechanisms against destructive environmental influences and to facilitate regenerative processes. No other cell type of the brain is endowed with a comparably comprehensive, immunocompetent machinery like microglia. It encompasses cell proliferation, migration and differentiation into full-blown macrophages able to present antigen and to phagocytose cell debris. Relatively little is known about these stages of microglia activation on the cellular and molecular level, although microglia have been described as a separate cell type of the brain as early as in the 30ies of this century by P.del Rio Hortega. This review summarizes the data that have accumulated until now in this respect and tries to embed them into a clinical framework. Special focus has been given to the role of this cell type in the development and progression of Multiple Sclerosis, HIV-associated dementia and Alzheimer's disease.

AIDS Dementia Complex↗
PubMed1998

Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6.

Interleukin-6 (IL-6) is a proinflammatory cytokine whose synthesis is induced by a variety of stimuli including interleukin-1 (IL-1), substance P (SP), and histamine. Because IL-6 has been implicated in the etiopathology of different human diseases including multiple myeloma, rheumatoid arthritis, multiple sclerosis, acquired immunodeficiency syndrome dementia complex, and Alzheimer's disease, its inhibition may be of therapeutic interest. A main demand on an effective inhibitor of IL-6 expression is that it inhibits IL-6 synthesis independently of the inducing stimulus. We therefore used human astrocytoma cells to search for signal transduction cascades and transcription factors whose inhibition suppresses IL-6 synthesis after stimulation with three different inductors, IL-1beta, SP, and histamine. Whereas the antioxidant pyrrolidinedithiocarbamate was only able to inhibit IL-1beta-induced IL-6 expression, inhibition of protein kinase C prevented IL-6 expression induced by all three substances. Promoter deletion analysis revealed that IL-1beta-induced IL-6 expression required the transcription factor nuclear factor-kappaB (NF-kappaB), whereas SP- and histamine-induced IL-6 synthesis was essentially controlled by NF-IL-6. These findings suggest that inhibition of protein kinase C or a combinatory inhibition of NF-IL-6 and NF-kappaB binding are strategies to effectively suppress IL-6 synthesis. They therefore provide the basis for the development of antiinflammatory drugs used to treat disorders in which IL-6 is pathogenically involved.

Astrocytoma↗
PubMed1998

Potential link between interleukin-6 and arachidonic acid metabolism in Alzheimer's disease.

Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD). Previously, we detected the presence of IL-6 in cortices of AD patients. On the other hand, non-steroidal antiinflammatory drugs (NSAIDs), potent inhibitors of prostaglandin synthesis, have been shown to be beneficial in the treatment of AD. Until now, it remained unclear whether and how these two observations were functionally connected. Here, we show that PGs are able to induce IL-6 synthesis in a human astrocytoma cell line. PGE1 and PGE2, but not PGD2 and PGF2 alpha, led to a rapid and transient induction of astrocytic IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1 beta-induced IL-6 mRNA synthesis. These results suggest a possible link between the release of PGs from activated microglia and the astrocytic synthesis of IL-6, which itself may affect neuronal cells, as hypothesized for Alzheimer's disease. Finally we demonstrate that microglia are a strong source of PGE2 synthesis indicating that these cells may act as the origin of the pathogenic cascade.

Alprostadil↗
PubMed1997

The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells.

The neuropeptide substance P is a major mediator of neurogenic inflammation and immunomodulatory activities within the central and peripheral nervous system. In several cell types, substance P induces the expression of proinflammatory cytokines that have been implicated in the pathogenesis of different neuropathologies. Substance P preferentially binds to NK-1, a receptor of the neurokinin family, but how the receptor-elicited signal is translated into inflammatory gene expression is not yet understood. In this work, we describe that in U373 MG astrocytoma cells, nanomolar concentrations of substance P potently triggered activation of NF-kappa B, a transcription factor involved in the control of cytokine expression and apoptosis. Substance P-induced NF-kappa B activation was associated with the increased mRNA expression and secretion of IL-8, an NF-kappa B-controlled target gene. The stimulatory effect of substance P was specific, since an NK-1-selective receptor antagonist completely prevented NF-kappa B activation in response to substance P, but not IL-1 beta. In addition, we show that the activity of substance P required mobilization of intracellular calcium and formation of reactive oxygen intermediates as second messengers. Our results suggest that NF-kappa B may be an important component controlling neurogenic inflammation within the peripheral and central nervous system.

Astrocytoma↗
PubMed1997

Expression and regulation of cyclooxygenase-2 in rat microglia.

Increased levels of prostanoids have been implicated in various neuropathological diseases, although little is known about their cellular sources inside the brain. In this study, we analyzed the expression of cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, in rat microglia. COX-2 mRNA and protein as well as prostaglandin E2 formation were almost undetectable in unstimulated microglial cultures but were found to be strongly upregulated in response to lipopolysaccharide. However, in contrast to most peripheral cells, proinflammatory cytokines such as tumor necrosis factor alpha, interleukin-1 beta or interleukin-6 failed to markedly induce COX-2 expression. Similar effects were observed by analyzing transcription nuclear factor-kappa B (NF-kappa B) which was strongly activated in microglia by lipopolysaccharide but not by incubation with cytokines. Moreover, known inhibitors of NF-kappa B activation, such as dexamethasone and the antioxidant pyrrolidine dithiocarbamate, as well as the protein kinase C (PKC) inhibitor Gö6976, strongly reduced lipopolysaccharide-induced COX-2 transcription, indicating the involvement of NF-kappa B and PKC in COX-2 expression. Our results suggest that microglia may represent an important source of prostanoids in the brain, thus reinforcing their prominent role in cerebral inflammatory processes.

Animals↗
PubMed1997

[Systemic immunologic diseases as differential diagnosis in psychiatry].

Psychiatric symptoms may be caused by systemic autoimmune diseases. Quite often, mental disorders are an early symptom during the course of an autoimmune disease and sometimes they may even be the presenting symptom. This article reviews psychiatric and neurologic symptoms in systemic lupus erythematodes, Sjögren syndrome, primary vasculitides and other immunopathies such as the primary antiphospholipid syndrome and Sneddon's syndrome. The article also discusses diagnostic aspects and therapeutic options if an autoimmune disease as cause of a psychiatric or neurologic symptom is suspected. An increased awareness of psychiatrists and neurologists will make it possible that systemic autoimmune diseases are early identified as a possible cause of psychiatric symptoms and may then be treated adequately.

Autoantibodies↗
PubMed1997

Potent inhibition of interleukin-6 expression in a human astrocytoma cell line by tenidap.

Tenidap is a structurally novel antirheumatic agent with anti-inflammatory and analgesic properties. Previous studies have shown that tenidap is able to inhibit the production and action of cytokines such as interleukin-1, interleukin-6 (IL-6) and tumour necrosis factor alpha. However, the mechanisms by which tenidap inhibits cytokine synthesis are not yet known. We investigated in the human astrocytoma cell line U373 whether tenidap inhibits IL-6 synthesis by inhibition of certain signal transduction processes leading to IL-6 synthesis. Cells were stimulated with different substances which have previously been shown to activate protein kinase A or C, reactive oxygen intermediates as well as transcription factors such as nuclear factor kappa B and AP-1 and which all result in IL-6 synthesis. Tenidap was a very potent inhibitor of IL-6 synthesis independent of the stimuli used, suggesting an inhibitory mechanism other than inhibition of a certain signal transduction pathway. Since IL-6 has been shown to be involved in the etiopathology of Alzheimer's disease and since the use of nonsteroidal anti-inflammatory drugs appears to be of therapeutical benefit, it is concluded that tenidap should be tested in clinical trials in order to determine whether it may be useful for the treatment of Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Prostaglandin E2 induces interleukin-6 synthesis in human astrocytoma cells.

Prostaglandins (PGs) and cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), have been implicated in the etiopathology of various inflammatory and degenerative disorders, including Alzheimer's disease (AD) and prion diseases. Nonsteroidal antiinflammatory drugs (NSAIDs), potent inhibitors of PG synthesis, appear to be beneficial in the treatment of AD. To assess whether PGs are able to induce IL-6 synthesis in cells of the CNS, IL-6 mRNA and protein syntheses were measured in a human astrocytoma cell line after stimulation with different PGs. PGE1 and PGE2, but not PGD2 and PGF2 alpha, led to a rapid and transient induction of IL-6 mRNA, followed by IL-6 protein synthesis. Furthermore, PGE2 potentiated IL-1 beta-induced IL-6 mRNA synthesis. These results are discussed with respect to the participation of PGs in neurodegenerative diseases (and its inhibition by NSAIDs) by affecting cytokine expression.

Alprostadil↗
PubMed1996

[Dementias--diagnosis, differential diagnosis and therapy].

The most common cause of primary (degenerative) dementia in old age is Alzheimer's disease, with vascular forms of dementia taking second place. Endocrinopathies, normal pressure hydrocephalus and space-occupying lesions are frequent causes of secondary dementia. A multitude of further, more rare clinical presentations results in a wide differential diagnostic spectrum necessitating a careful diagnostic work-up of the demential syndrome before considering treatment. This work-up must include clinical, laboratory and equipment-based investigations. The multimodal therapeutic approach to dementia covers not only the elimination of treatable underlying causal conditions and the medical treatment of cognitive symptoms and psychiatric accompanying symptoms, but also non-medicamentous aspects.

Alzheimer Disease↗
PubMed1996

Preattentive information processing as measured by backward masking and texton detection tasks in adolescents at high genetic risk for schizophrenia.

Schizophrenic patients have consistently been reported to show deficits in preattentive information processing as demonstrated by impairments in visual backward masking and texton detection tasks. Texton detection refers to Julesz's texton theory, which defines a certain limited number of texton elements (e.g., one 'L' among many '+') that can be detected readily and simultaneously without attentional effort irrespective of the size of the rest of the visual field. The present study investigated whether deficits of preattentive information processing are more prevalent in a group of adolescents of high genetic risk for schizophrenia compared to matched control subjects. Although differences in the performance in visual backward masking tasks could not be detected with our experimental approach, preattentive texton detection was to a certain extent disturbed in subjects at risk. Moreover, subjects at risk did not show the advantage of the right hemisphere in processing texton elements which was found in the control group. This may point to a subtle dysfunction of the right hemisphere in the risk group. It is concluded from the present study that deficits in preattentive texton detection may represent an indicator for a schizophrenic disposition. However, further studies including other high risk groups, schizophrenics in remission and individuals with a schizotypal personality disorder are needed to confirm this hypothesis.

Adolescent↗
PubMed1996

Pre- and postnatal development of dopaminergic neuron numbers in the male and female mouse midbrain.

Quantitative information about dopaminergic neuron numbers in the mesencephalon is needed to assess the significance of physiological cell death in the regulation of the development of this neural system. Therefore, stereological techniques were applied to determine absolute numbers of mesencephalic neurons immunoreactive to tyrosine hydroxylase during the ontogenetic period between embryonic day (E) 13 and postnatal day (P) 90. Male and female CBA/J mice were examined separately. The most rapid development with a 2.5-fold increase of total counts of immunostained cells per midbrain took place in the prenatal period. Beginning at E21, immunostained cells were counted separately in their three main locations, substantia nigra (SN), ventral tegmental area (VTA), and retrorubral field (RRF). Neuron numbers in RRF and VTA reached adult levels perinatally. In contrast, counts of immunostained cells in SN continued to increase postnatally. The only sign of cell loss was a transient decrease in VTA cell numbers (but not in total numbers of immunostained midbrain neurons) between E21 and P14. There were no statistically significant sex differences in cell numbers at any time point investigated. It is concluded that physiological cell death is not a major factor in the developmental regulation of dopaminergic cell numbers in the mouse midbrain.

Animals↗
PubMed1996

Effects of NSAIDs on IL-1 beta-induced IL-6 mRNA and protein synthesis in human astrocytoma cells.

Inflammatory processes contribute to the aetiopathology of Alzheimer's disease (AD). Interleukin-6 (IL-6), a proinflammatory cytokine, is found in the brains of AD patients, but not in brains of normal control persons. In the present study, the effects of seven non-steroidal anti-inflammatory drugs (NSAIDs) on interleukin-1 beta (IL-1 beta)-induced IL-6 mRNA expression and protein synthesis in a human astrocytoma cell line were investigated. Tenidap, naproxen and meloxicam inhibited the IL-1 beta-induced synthesis of IL-6, whereas ibuprofen, piroxicam, diclofenac and indomethacin had no effect. While the effects of naproxen and meloxicam were small and restricted to protein synthesis, tenidap strongly inhibited IL-6 protein synthesis and also affected IL-6 mRNA levels. It is concluded that NSAIDs, and particularly tenidap, may be useful for the treatment of inflammatory processes associated with AD.

Anti-Inflammatory Agents, Non-Steroidal↗
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↗