Biomedical subjects

M Krug

Publications and source records attributed to M Krug.

At least 19 recordsLinked to original sources

PubMed2004

[Addiction to tobacco and the consequences for the skin].

Consumption of tobacco is hazardous to the health. It leads to cardiovascular diseases, and increases the incidence of numerous neoplasms. The adverse effects on the skin are less well-known and often ignored. Changes in the rheologic characteristics of the blood, increased vasoconstriction and damage to the epithelial layer of the vessel play an important pathogenic role in impaired wound healing, thromboangiitis obliterans and peripheral arterial obstructive diseases. Interactions with collagen metabolism are of special significance in wound healing and skin aging. The immunological effects, such as the induction of an inflammation reaction play a role in palmoplantar pustulosis, psoriasis, atopic dermatitis, acne vulgaris, acne inversa, thromboangiitis obliterans and lupus erythematodes. In addition, immunosuppression caused by nicotine consumption may contribute to the pathogenesis of human papilloma-virus infections, malignant melanoma and epithelial tumors of the skin and neighboring mucous membranes.

Estrogens↗

PubMed2003

NCAM180 and glutamate receptor subtypes in potentiated spine synapses: an immunogold electron microscopic study.

Activity-dependent changes in expression and localization of the largest major isoform of the neural cell adhesion molecule NCAM180 and three subtypes of glutamate receptors predominantly expressed in the outer part of the molecular layer of the dentate gyrus of adult rats-the NMDA receptor NR2A, the AMPA receptor GluR2/3, and the metabotropic glutamate receptor mGluR1 - were investigated using postembedding immunogold labeling, and electron microscopy. In synaptic membranes of nonstimulated spine synapses, NCAM180 and NR2A accumulated in the center of the postsynaptic density, whereas GluR2/3 and mGluR1 were distributed evenly. Twenty-four hours following induction of long-term potentiation in vivo, NCAM180 and NR2A accumulated at the edges of postsynaptic densities, whereas GluR2/3 was localized more centrally. Also, the distribution of gold particles per synapse significantly changed for NCAM180, NR2A, and mGluR1. Thus, changes in synaptic strength are associated with concomitant changes in the expression and distribution of NCAM180 and glutamate receptors, particularly of the NR2A subtype.

Animals↗

PubMed2001

Early effects on restoration of evoked field potentials in the hippocampal CA(1) region after reversible hypoxia/hypoglycemia by the radical scavenger N-tert.-butyl-alpha-phenylnitron.

In transverse hippocampus slices a short period of hypoxia/hypoglycemia induced by perfusion with an O(2)/glucose-free medium caused early loss and incomplete restoration of evoked field potentials in the CA(1) region. In the present study a search was made for whether the formation of free oxoradicals immediately after starting the hypoxic phase could be part of the breakdown and incomplete restoration of the excitatory potentials (EPs). It was shown that preincubation and postischemic incubation with the radical scavenger PBN did not prevent the potential breakdown but significantly enhances potential restoration, even when PBN was added to the perfusion medium 40 min after hypoxia. Thus, free oxoradicals may damage membrane constituents such as receptors or channel proteins at a very early phase, before neuronal death is pronounced. The results also show that treatment with radical scavengers has a beneficial effect on early hypoxic damage.

Animals↗

PubMed2001

Immunoelectron microscopic localization of the neural recognition molecules L1, NCAM, and its isoform NCAM180, the NCAM-associated polysialic acid, beta1 integrin and the extracellular matrix molecule tenascin-R in synapses of the adult rat hippocampus.

We have investigated the possibility that morphologically different excitatory glutamatergic synapses of the "trisynaptic circuit" in the adult rodent hippocampus, which display different types of long-term potentiation (LTP), may express the immunoglobulin superfamily recognition molecules L1 and NCAM, the extracellular matrix molecule tenascin-R, and the extracellular matrix receptor constituent beta1 integrin in a differential manner. The neural cell adhesion molecules L1, NCAM (all three major isoforms), NCAM180 (the largest major isoform with the longest cytoplasmic domain), beta1 integrin, polysialic acid (PSA) associated with NCAM, and tenascin-R were localized by pre-embedding immunostaining procedures in the CA3/CA4 region (mossy fiber synapses) and in the dentate gyrus (spine synapses) of the adult rat hippocampus. Synaptic membranes of mossy fiber synapses where LTP is expressed presynaptically did not show detectable levels of immunoreactivity for any of the molecules/epitopes studied. L1, NCAM, and PSA, but not NCAM180 or beta1 integrin, were detectable on axonal membranes of fasciculating mossy fibers. In contrast to mossy fiber synapses, spine synapses in the outer third of the molecular layer of the dentate gyrus, which display postsynaptic expression mechanisms of LTP, were both immunopositive and immunonegative for NCAM, NCAM180, beta1 integrin, and PSA. Those spine synapses postsynaptically immunoreactive for NCAM or PSA also showed immunoreactivity on their presynaptic membranes. NCAM180 was not detectable presynaptically in spine synapses. L1 could not be found in spine synapses either pre- or postsynaptically. Also, the extracellular matrix molecule tenascin-R was not detectable in synaptic clefts of all synapses tested, but was amply present between fasciculating axons, axon-astrocyte contact areas, and astrocytic gap junctions. Differences in expression of the membrane-bound adhesion molecules at both types of synapses may reflect the different mechanisms for induction and/or maintenance of synaptic plasticity.

Animals↗

PubMed2001

Simultaneous activation and opioid modulation of long-term potentiation in the dentate gyrus and the hippocampal CA3 region after stimulation of the perforant pathway in freely moving rats.

Recent investigations indicate monosynaptic activation by the perforant pathway (pp) of the dentate gyrus and the CA3 region. While short-term potentiation and long-term potentiation (LTP) and its opioid modulation are frequently described for the dentate gyrus, data for the CA3 region are rare. Therefore, evoked potentials and opioid modulation of LTP were directly compared in both target regions of the pp. Male Wistar rats were chronically implanted with a bipolar stimulation electrode in the pp (angular bundle) and two recording electrodes in the dorsal dentate gyrus and the CA3 region. Stimulation of the pp in the freely behaving animals induced short-latency evoked potentials in both target structures which were compared with respect to waveform, latency, amplitude and signs of short- and long-term neuronal plasticity. The short-latency potential in the CA3 region seemed to be a monosynaptic potential which displayed LTP sensitive to the N-methyl-D-aspartate receptor antagonist, MK 801, and depotentiating stimulation. After application of specific opioid antagonists at the mu-, delta- and kappa-opioid receptor subtypes, naloxone, funaltrexamine, naltrindole and binaltorphimine, different effects on induction and maintenance of LTP of the population spike were found both within the dentate gyrus and between the dentate gyrus and the CA3 region. The results show marked diminution of LTP in the dentate gyrus only for naloxone and naltrindole and only small, if any, effects of naloxone on LTP in the CA3 region. Thus, neuronal plasticity in the direct perforant pathway input to the CA3 region seems not to be under such substantial opioidergic control. LTP would be inducible in that region even when LTP in the input formation, the dentate gyrus, and transsynaptic LTP via the mossy fibres are blocked.

Animals↗

PubMed2001

Discriminating between drugs and nondrugs by prediction of activity spectra for substances (PASS).

Using the computer system PASS (prediction of activity spectra for substances), which predicts simultaneously several hundreds of biological activities, a training set for discriminating between drugs and nondrugs is created. For the training set, two subsets of databases of drugs and nondrugs (a subset of the World Drug Index, WDI, vs the Available Chemicals Directory, ACD) are used. The high value of prediction accuracy shows that the chemical descriptors and algorithms used in PASS provide highly robust structure-activity relationships and reliable predictions. Compared to other methods applied in this field, the direct benchmark undertaken with this paper showed that the results obtained with PASS are in good accordance with these approaches. In addition, it has been shown that the more specific drug information used in the training set of PASS, the more specific discrimination between drug and nondrug can be obtained.

Computer Simulation↗

PubMed2001

Activation of the dentate gyrus by stimulation of the contralateral perforant pathway: evoked potentials and long-term potentiation after ipsi- and contralateral induction.

Rats were chronically implanted with stimulation electrodes in the perforant pathway (pp) bilaterally and a recording electrode in the dentate gyrus (DG) unilaterally. Evoked field potentials (EPs) were recorded upon alternating stimulation of the pp on both sides, and long-term potentiation (LTP) was induced. Besides the EP after ipsilateral stimulation, an EP with a latency of approximately 5.5-6.5 ms was also seen upon stimulation of the contralateral pp. This potential was reversibly abolished during pentobarbital anesthesia and irreversibly after lesioning of the ipsilateral angular bundle. Paired-pulse facilitation and paired-pulse depression, depending on interstimulus interval and intensity, were also observed. Therefore, this long-latency potential could be characterized as polysynaptic and induced perhaps by transsynaptic activation via the ipsilateral entorhinal cortex. Ipsilateral tetanization induced strong E/S potentiation of both the ipsilaterally and contralaterally evoked EP, but with different time courses. Tetanization of the contralateral pp did not induce LTP of the ipsilaterally induced EP in the first 4 h. But afterwards a late and slowly developing potentiation occurred. The contralaterally induced EP also showed potentiation of the population spike, which was not immediately detectable but developed slowly over time. The results can be interpreted such that, after stimulation of the pp, the DG on the opposite side cannot only be activated via the weak crossed entorhinal projection but also transsynaptically via an entorhino/entorhinal connection.

Animals↗

PubMed2001

Development of long-lasting potentiation effects in the dentate gyrus during pentylenetetrazol kindling.

In the present study kindling was induced in rats by repeated intraperitoneal injection of pentylenetetrazol (PTZ) once every 48 h. The resulting seizure stages were registered after each PTZ application. The development of PTZ-induced kindling and the time course of possible potentiation effects in the dentate gyrus were examined. The efficacy of perforant pathway transmission to the granule cells was tested in every second kindling session by measuring the monosynaptic evoked field potentials recorded in the dentate gyrus following single test stimuli of the perforant pathway at different times after PTZ injection in freely moving animals. The data suggest that establishment of a PTZ kindling is associated with the development of long-lasting potentiation of the field potentials. After completion of kindling it was demonstrated that kindled rats also show a diminished learning performance. The relationship between the development of potentiation phenomena in hippocampal substructures and learning impairment is discussed.

Animals↗

PubMed2001

Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia.

A variety of extracellular serine proteases are expressed in the central nervous system or might permeate the blood-brain barrier under pathological conditions. However, their intracerebral targets and physiological functions are largely unknown. Here, we show that four distinct subtypes of protease-activated receptors (PARs) are abundantly expressed in the adult rat brain and in organotypic hippocampal slice cultures. PAR-1 expression was significant in the hippocampus, cortex and amygdala. Highest densities of PAR-2 and PAR-3 were observed in hippocampus, cortex, amygdala, thalamus, hypothalamus and striatum. Apart from the striatum, a similar localization was found for PAR-4. Within the hippocampal formation, each PAR subtype was predominantly localized in the pyramidal cell layers. Additionally, we identified PAR-2 in mossy fibers between dentate gyrus and CA3, PAR-3 in the subiculum and PAR-4 in CA3 and in mossy fibres as well as in the stratum lacunosum moleculare. After exposing hippocampal slice cultures to a severe experimental ischemia (oxygen-glucose deprivation), the expression of PARs 1-3 was up-regulated with subtype-specific kinetics. The localization of PARs in brain regions particularly vulnerable to ischemic insults as well as distinct alterations in the expression pattern after experimental ischemia support the notion of an important role of extracellular serine proteases and PARs in cerebral ischemia.

Animals↗

PubMed2001

Neurocan is dispensable for brain development.

Neurocan is a component of the extracellular matrix in brain. Due to its inhibition of neuronal adhesion and outgrowth in vitro and its expression pattern in vivo it was suggested to play an important role in axon guidance and neurite growth. To study the role of neurocan in brain development we generated neurocan-deficient mice by targeted disruption of the neurocan gene. These mice are viable and fertile and have no obvious deficits in reproduction and general performance. Brain anatomy, morphology, and ultrastructure are similar to those of wild-type mice. Perineuronal nets surrounding neurons appear largely normal. Mild deficits in synaptic plasticity may exist, as maintenance of late-phase hippocampal long-term potentiation is reduced. These data indicate that neurocan has either a redundant or a more subtle function in the development of the brain.

Animals↗

PubMed2001

Conditioning hypoxia in vivo alters neuronal excitability of hippocampal neurones of rats in vitro and in vivo.

PURPOSE: Moderate normobaric hypoxia causes long-lasting protection against damage induced by a second ischemic or traumatic insult. The changes induced by such conditioning hypoxia are not yet fully understood. The protective effect has been described in various publications but other effects seem possible. METHODS: In order to search for effects of conditioning normobaric hypoxia yet unknown, we measured O-Mg++ potentiation and classical long-term potentiation (LTP) in the CA, region of hippocampal slices seven days after the conditioning procedure. Furthermore, tests were also carried out in chronically implanted rats as to whether LTP was changed in the dentate gyrus after conditioning hypoxia. RESULTS: In slices taken from animals which received conditioning hypoxia, O-Mg++ potentiation and classical LTP of the population spike were significantly enhanced, when compared to population in two control groups. Anoxic LTP, i.e. increase in the population spike of the field potential in the dentate gyrus immediately after finishing the procedure, and a tendency to elevation of LTP seven days after conditioning were also found in chronically implanted animals which were subjected to conditioning hypoxia. CONCLUSIONS: lt. may be hypothesized that elevated Ca++ transport in the neurons during conditioning hypoxia is responsible for both long- lasting increases in plastic reactions and the protective effect.

Animals↗

PubMed2000

Does fucose or piracetam modify the effect of hypoxia preconditioning against pentylenetetrazol-induced seizures?

To clarify the question whether the duration of hypoxia exposure has an influence on the point in time or the strength of hypoxic preconditioning, hypoxia exposure of rats lasting 1 and 8 h was tested regarding the modification of susceptibility to acute pentylenetetrazol-induced seizures. Following the short-lasting (1 h) hypoxia, the maximum level of preconditioning action was observed 7 days after hypoxia, whereas the longer-lasting hypoxia (8 h) produced the maximum level of protection 14 days after hypoxia. We investigated the influence of fucose and piracetam on the effect of hypoxia preconditioning by the application of the substances 20 min before the beginning of hypoxia exposure. Fucose did not modify the result of hypoxia preconditioning. But after the treatment with piracetam, the preconditioning effect was prevented following hypoxia lasting 1 and 8 h. We suggest that the radical scavenger properties of piracetam are responsible for the absence of protection against pentylenetetrazol-evoked seizures.

Animals↗

PubMed2000

Delayed onset of late movement-related cortical potentials and abnormal response to lorazepam in catatonia.

Catatonia is a psychomotor syndrome with an inability to execute and terminate movements completely, leading consecutively to akinesia and posturing, which both respond almost immediately to benzodiazepines, i.e. gaba-potentiators like lorazepam. However, pathophysiological mechanisms of cortical motor and gaba-ergic dysfunction remain unclear. We therefore investigated movement-related cortical potentials (MRPs) and movement kinematics during a motor task before and after lorazepam. Ten akinetic catatonic patients were compared with 10 psychiatric (similar age, sex, medication, and underlying psychiatric disease but without catatonic syndrome) and 20 healthy controls. MRPs from frontal (F), central (C), and parietal (P) sites were recorded to obtain measures of early and late readiness potential and movement potential. Kinematic measures included parameters for amplitude of movements, peak velocity, average duration of movements, elevation angle, and angle velocity. The motor task consisted in self-initiated extension of the right index finger. All catatonic and psychiatric control patients received intravenous lorazepam (1mg), whereas healthy controls were subjected to a placebo-controlled (10 received lorazepam, 10 received placebo) double-blind study design.Catatonics showed a significantly delayed onset of late readiness and movement potential in central electrodes (Cz, C3) compared with psychiatric and healthy controls. This delayed onset correlated significantly with catatonic motor symptoms and movement duration. Lorazepam led to significantly stronger delays in onset of late readiness potential in left fronto-parietal (F3, C3, P3) electrodes in catatonic patients than in psychiatric and healthy controls. It is concluded that delayed latencies in late MRP components in catatonic patients may reflect their inability to execute and terminate movements completely. Differential and stronger response to lorazepam in catatonia suggests dysfunction in inhibitory control of cortical motor function with increased gaba-ergic sensitivity.

Adult↗

PubMed2000

The importance of free hydroxyl radicals to hypoxia preconditioning.

Hypoxia preconditioning states that a sublethal hypoxia period will afford neuroprotection against a second harmful event. In our experiments, we carried out a procedure for the development of hypoxia preconditioning in adult male Wistar rats using hypoxic exposure (9% O(2); 91% N(2)) for 1 h. The protection against pentylenetetrazol (PTZ)-induced seizures was studied. For this, rats were tested by a single injection of PTZ (55 mg/kg i.p.) on days 1-21 after hypoxia exposure. The hypoxia exposure significantly prevented the development of acute PTZ convulsion at different times after hypoxia. The present study was designed to determine the effect of N-t-butyl-alpha-phenylnitrone (PBN), an electron-trapping agent and free radical scavenger, on hypoxia preconditioning against PTZ seizures 7 days after hypoxia exposure. PBN abolished the protective action of hypoxia exposure. The generation of free hydroxyl radicals in the brains of animals exposed to hypoxia was determined in a second experiment. For this purpose, the rats were i. p. pretreated with 30 mg/kg PBN and NaCl, respectively, 20 min before the start of hypoxia exposure. Forty-five minutes later the rats were i.p. injected with 300 mg/kg sodium salicylate and once again exposed to hypoxia for 15 min. Immediately after that the animals were decapitated and the free hydroxyl radicals and the salicylate content were estimated in the whole brain without cerebellum. Hypoxia preconditioned animals pretreated with NaCl showed a significantly higher extent of free hydroxyl radicals in the brain compared with PBN-injected preconditioned animals and with naive and sham exposed controls. The results pointed out that the generation of free reactive oxygen species under hypoxic conditions in the brain is involved in the development of the hypoxic preconditioning phenomenon.

Animals↗

PubMed2000

The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses.

Neuroplastin-65 and -55 (previously known as gp65 and gp55) are glycoproteins of the Ig superfamily that are enriched in rat forebrain synaptic membrane preparations. Whereas the two-Ig domain isoform neuroplastin-55 is expressed in many tissues, the three-Ig domain isoform neuroplastin-65 is brain-specific and enriched in postsynaptic density (PSD) protein preparations. Here, we have assessed the function of neuroplastin in long-term synaptic plasticity. Immunocytochemical studies with neuroplastin-65-specific antibodies differentially stain distinct synaptic neuropil regions of the rat hippocampus with most prominent immunoreactivity in the CA1 region and the proximal molecular layer of the dentate gyrus. Kainate-induced seizures cause a significant enhancement of neuroplastin-65 association with PSDs. Similarly, long-term potentiation (LTP) of CA1 synapses in hippocampal slices enhanced the association of neuroplastin-65 with a detergent-insoluble PSD-enriched protein fraction. Several antibodies against the neuroplastins, including one specific for neuroplastin-65, inhibited the maintenance of LTP. A similar effect was observed when recombinant fusion protein containing the three extracellular Ig domains of neuroplastin-65 was applied to hippocampal slices before LTP induction. Microsphere binding experiments using neuroplastin-F(c) chimeric proteins show that constructs containing Ig1-3 or Ig1 domains, but not Ig2-3 domains mediate homophilic adhesion. These data suggest that neuroplastin plays an essential role in implementing long-term changes in synaptic activity, possibly by means of a homophilic adhesion mechanism.

Animals↗

PubMed2000

Lack of expression of long-term potentiation in the dentate gyrus but not in the CA1 region of the hippocampus of mu-opioid receptor-deficient mice.

The possible involvement of the mu-opioid receptor subtype in mechanisms of long-term potentiation (LTP) of the lateral perforant pathway to the dentate gyrus neurons, as well as of the Schaffer collateral-commissural input of CA1 neurons, was investigated using mu-opioid receptor-deficient mutant mice. In transversal hippocampal slices from mice lacking the mu-opioid receptor (MOR) only a short potentiation in the dentate gyrus after tetanization of the lateral perforant pathway was found. In contrast, the loss of the mu-opioid receptor in the CA1 region did not affect the potentiation of the field potentials induced by tetanization of the Schaffer collaterals. In parallel experiments, the application of 10 microM of the selective MOR-antagonist, funaltrexamine, decreased LTP in the dentate gyrus of wild-type mice but again did not alter the potentiation of the field potentials in the CA1. The loss of MOR-binding in the hippocampus was accompanied by a reduction in D2-binding sites indicating a possible compensatory role of the dopaminergic system. The D1- and glutamate binding was not affected. These observations confirm earlier results with pharmacological blockade of opioid receptors in the dentate gyrus and demonstrate an essential role of MOR activation for the generation of LTP in the dentate gyrus of the mouse but not necessarily in the CA1 region.

Action Potentials↗

PubMed2000

Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol.

Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.

Action Potentials↗

PubMed1999

Direct evidence for biphasic cAMP responsive element-binding protein phosphorylation during long-term potentiation in the rat dentate gyrus in vivo.

Phosphorylation of the transcription factor cAMP responsive element-binding protein (CREB) is thought to play a key role in synaptic plasticity and long-term memory. However, direct evidence for CREB phosphorylation during hippocampal long-term potentiation (LTP) in vivo is sparse. Here, we show that, in the intact animal, CREB is rapidly phosphorylated in response to high-frequency stimulation but not low-frequency stimulation of the perforant pathway. CREB phosphorylation occurred in a biphasic manner, with a first peak at 30 min and a second long-lasting peak beginning 2 hr after tetanic stimulation and lasting for at least 24 hr. Only stimuli that generated nondecremental LTP promoted a sustained hyperphosphorylation of CREB but not stimuli that produced decremental LTP. CREB phosphorylation was specifically triggered in the dentate gyrus, as well as the CA1, but not the CA3, hippocampal region. Pretreatment with the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate completely prevented activation of CREB. Together, we have resolved the spatial and temporal dynamics of CREB phosphorylation during hippocampal LTP, showing that the transcription factor CREB is specifically recruited at two distinct time points in some forms of hippocampal synaptic plasticity in vivo.

Animals↗