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K Lieb

Publications and source records attributed to K Lieb.

At least 19 recordsLinked to original sources
PubMed2001

Borna disease virus--does it infect humans and cause psychiatric disorders?

Antibodies recognizing Borna disease virus (BDV) antigens were first demonstrated in the blood of psychiatric patients approximately 15 years ago. Since that time, a highly controversial debate arose whether BDV infects humans and whether it causes psychiatric disorders. In this review, we critically discuss the results of numerous studies that assessed this possibility by using virological and serological methods. We conclude that there is presently no strong experimental evidence supporting the notion that BDV is a human pathogen. The possibility remains, however, that an antigenically related agent is associated with human psychiatric disorders.

Amantadine↗
PubMed2001

Inhibition of substance P-induced cytokine synthesis by St. John's wort extracts.

We tested the hypothesis that extracts from St. John's wort interfere with protein synthesis induced by substance P (SP), a neuropeptide which has been implicated in the etiopathology of depression and anxiety. Using human astrocytoma cells, which express functional neurokinin (NK)-1-receptors, we investigated whether extracts from St. John's wort are able to inhibit SP-induced synthesis of the cytokine interleukin-6 (IL-6). We found a potent and dose-dependent inhibition of SP-induced IL-6 synthesis by various extracts from St. John's wort. These results do not only give further evidence of the anti-inflammatory effects of St. John's wort, but also lend support to the hypothesis that the antidepressant effect of St. John's wort is, at least in part, a result of its inhibitory effects on SP-induced protein synthesis.

Antidepressive Agents↗
PubMed2000

The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B.

Substance P (SP), a member of the tachykinin peptide family, is a major mediator of neuroimmunomodulatory activities and neurogenic inflammation within the central and peripheral nervous system. SP has been shown to induce the expression of proinflammatory cytokines such as IL-6, which might be implicated in the etiopathology of several human brain disorders. We showed in a previous study that nanomolar concentrations of SP triggered activation of NF-kappaB, a transcription factor involved in the control of cytokine expression. However, activation of NF-kappaB was not involved in SP-induced expression of IL-6. Here, we describe p38 mitogen-activated protein kinase (p38 MAPK) as a signal transduction component that operates independently from NF-kappaB activation and that mediates SP-induced IL-6 expression in the human astrocytoma cell line U373 MG. SP induced the phosphorylation of p38 MAPK within 10 min, and this activation persisted up to 30 min and was independent from p42/44 MAPKs and protein kinase C activation, which all are induced after stimulation with SP. As shown by EMSA, p38 MAPK was not involved in SP-induced activation of NF-kappaB. p38 MAPK, however, mediated SP-induced IL-6 expression as shown by the use of specific inhibitors of this kinase. Our results suggest that activation of p38 MAPK is an important component controlling neurogenic inflammation within the CNS independently from NF-kappaB. Drugs targeting this MAPK may therefore interfere with SP-correlated neuropsychiatric disorders and may represent a therapeutic approach in these disorders.

Astrocytoma↗
PubMed2000

Pain perception during self-reported distress and calmness in patients with borderline personality disorder and self-mutilating behavior.

Self-mutilation occurs in 70-80% of patients who meet DSM-IV criteria for borderline personality disorder. Approximately 60% of these patients report that they do not feel pain during acts of self-mutilation such as cutting or burning. Findings of recent studies measuring pain perception in patients with BPD are difficult to interpret since variables such as distress, dissociation or relevant psychotropic medication have not been controlled. The Cold Pressor Test (CPT) and the Tourniquet Pain Test (TPT) were administered to 12 female patients with BPD who reported analgesia during self-mutilation and 19 age-matched healthy female control subjects. All subjects were free of psychotropic medication. The patients were studied on two occasions: during self-reported calmness and during intensive distress (strong urge to cut or burn themselves). Even during self-reported calmness, patients with BPD showed a significantly reduced perception of pain compared to healthy control subjects in both tests. During distress, pain perception in BPD patients was further significantly reduced as compared with self-reported calmness. The present findings show that self-mutilating patients with BPD who experience analgesia during self-injury show an increased threshold for pain perception even in the absence of distress. This may reflect a state-independent increased pain threshold which is further elevated during stress. Interpretation of these findings is limited by their reliance upon self-reports.

Adult↗
PubMed2000

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.

Acetaminophen↗
PubMed2000

Strategies to delay the onset of Alzheimer's disease.

Several processes are implicated in the neuropathology of Alzheimer's disease (AD), such as the deposition of amyloid, the formation of paired helical filaments and the proinflammatory activation of microglial and astroglial cells. Proinflammatory activation of glial cells has been a focus of research for a mere ten years now. However, the availability of and broad experience with anti-inflammatory drugs has led to several ongoing clinical trials to verify the capacity of anti-inflammatory drugs to ameliorate the deterioration in AD. The enzymatic cleavage of the amyloid-precursor-protein or the hyperphosphorylation of tau as well as the subsequent aggregation of the resulting products are further targets for drugs intended to delay the neuropathological destruction observed in AD.

Aged↗
PubMed2000

[Substance P receptor antagonists--a new antidepressive and anxiolytic mechanism?].

Preclinical investigations suggest that the neuropeptide substance P might be involved in the etiopathology of pain, depression, and anxiety. In a recent study, the substance P receptor antagonist MK-869 showed antidepressant and anxiolytic activity in depressed outpatients which was comparable to a standard SSRI. The MK-869 was well tolerated. Although these findings are promising, further studies are necessary to prove the hypothesis that substance P receptor antagonists represent a new class of antidepressants or anxiolytics. Respective studies are currently underway.

Anti-Anxiety Agents↗
PubMed2000

Prefrontal cortical hypometabolism during low-dose interferon alpha treatment.

OBJECTIVE: To evaluate prospectively interferon alpha (IFN-alpha) associated effects on cerebral glucose metabolism and its correlation to neuropsychiatric symptoms during low-dose IFN-alpha-treatment. METHODS: Eleven patients treated with low-dose IFN-alpha for chronic hepatitis C were prospectively evaluated by neuropsychiatric tests and cerebral [18F]deoxyglucose positron emission tomography (FDG-PET) before and in the 12th week of treatment. PET images were spatially normalized, corrected for variance in global activity and pixel-based t-statistics were calculated for each set of PET scans using SPM96 software. Pixel-cluster with P<0.001 for hypo- or hypermetabolism were displayed in parametric images. Covariance analysis with neuropsychiatric tests was calculated for each cluster. RESULTS: In week 12 of IFN-alpha treatment, significant hypometabolism with a decrease of local activity ranging from 8 to 12% was found in all patients bilaterally in the prefrontal cortex (BA 9), which correlated in a covariate analysis with changes in depression score as measured by Beck's Depression Inventory. Additionally, hypermetabolism with a maximum increase in local activity of 6-8% was seen in all patients in putamina as well as the left occipital region (BA 18). Before IFN-alpha treatment, only 1/11 patient showed depressive symptomatology. After 3 months of treatment, 6/11 patients were classified as having mild to moderate depressive symptoms (P<0.1; Wilcoxon test). CONCLUSIONS: Low-dose IFN-alpha therapy is associated with significant prefrontal hypometabolism. This hypometabolism covaried with depression score, but was even found in clinically non-depressed patients. These findings may reflect a possible predisposing factor for IFN-alpha associated neuropsychiatric syndromes and might contribute to a pathophysiological model of affective disorders, as endogenous IFN-alpha levels are elevated in a subset of psychotic patients during acute disease.

Adult↗
PubMed2000

Protective role of neurotrophins in experimental inflammation of the rat gut.

BACKGROUND & AIMS: Sensory neuropeptides modulate the mucosal response to inflammation in experimental colitis. Because nerve growth factor (NGF) regulates the expression of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) and is implicated as a link between the nervous system and the immune system in the inflammatory process, we investigated the functional role of NGF and neurotrophin-3 during experimental colitis. METHODS: Immunoneutralizing antibodies specific for NGF and neurotrophin (NT)-3 were used to block their endogenous activity. Mild trinitrobenzene sulfonic acid (TNBS) colitis was induced, and damage scores were assessed after 1 week. Neuropeptide content in the colon and NT messenger RNA (mRNA) expression were determined. RESULTS: The pretreatment with anti-NGF or anti-NT-3 caused a significant 2-3-fold increase in the severity of the experimental inflammation as assessed by a macroscopic damage score, histologic ulceration score, and myeloperoxidase activity in the tissue. CGRP, but not substance P, contents in the colon were significantly reduced by NGF immunoneutralization. NGF mRNA was slightly up-regulated after NGF immunoneutralization, but NT-3 mRNA was unchanged by NT-3 immunoneutralization. CGRP mRNA was not significantly changed after 1 week of colitis by NGF or NT-3 immunoneutralization, whereas beta-preprotachykinin mRNA was up-regulated after immunoneutralization. CONCLUSIONS: These findings suggest a regulatory role for NGF and NT-3 in experimental inflammation of the gut. This effect may be partly caused by the reduction of mucosal CGRP content caused by the NGF blockade.

Animals↗
PubMed2000

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Journal Article↗
PubMed2000

Anti-inflammatory drugs: a hope for Alzheimer's disease?

Human brain cells are capable of initiating and amplifying a brain specific inflammatory response involving the synthesis of cytokines, acute-phase proteins, complement proteins, prostaglandins and oxygen radicals. In Alzheimer's disease (AD), all signs of an inflammatory microglial and astroglial activation are present inside and outside amyloid depositions and along axons of neurones with neurofibrillary tangles. Cell culture and animal models suggest a bidirectional relationship between inflammatory activation of glial cells and the deposition of amyloid. Although it remains unclear which of the different pathophysiological processes in AD may be the driving force in an individual case, the inflammatory activation may increase the speed of cognitive decline. Epidemiological studies point to a reduced risk of AD among users of anti-inflammatory drugs. Therefore, anti-inflammatory drugs have become the focus of several new treatment strategies. A clinical trial with the non-steroidal anti-inflammatory drug (NSAID) indomethacin showed promising results, while a clinical trial with steroids did not show a beneficial effect. Further trials with NSAIDs such as unselective cyclooxygenase (COX) and selective cyclooxygenase-2 (COX-2) inhibitors are on their way. COX inhibitors may not only act on microglial and astroglial cells but also reduce neuronal prostaglandin production. New data suggest that prostaglandins enhance neurotoxicity or induce pro-inflammatory cytokine synthesis in astroglial cells. Amongst these promising new strategies to reduce microglial or monocyte activation, interfering with intracellular pathways has been shown to be effective in various cell culture and animal models but clinical studies have not yet been performed.

Alzheimer Disease↗
PubMed1999

The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha.

Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic properties. Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as alpha1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappaB activation by tepoxalin is mediated by preventing IkappaB-alpha degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.

Alzheimer Disease↗
PubMed1999

Anti-inflammatory substances - a new therapeutic option in Alzheimer's disease.

Among several pathogenetic elements underlying Alzheimer's disease (AD), a brain-specific inflammatory response has recently attracted attention as a cause of neurodegeneration and progressive cognitive decline. Markers of inflammation in AD are activated microglial cells, synthesis of cytokines, acute-phase proteins and complement proteins in areas of brain destruction. Epidemiological studies point to a reduced risk of AD among users of anti-inflammatory drugs. Influencing inflammatory parameters has become the focus of several new treatment strategies and a clinical trial with indomethacin shows promising results. The results from current clinical trials with steroidal and non-steroidal anti-inflammatory drugs will be available in the near future.

Journal Article↗
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↗