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Biomedical subjects

G Stoll

Publications and source records attributed to G Stoll.

At least 37 records · Page 2Linked to original sources
PubMed2000

Time course of inwardly rectifying K(+) current reduction in glial cells surrounding ischemic brain lesions.

K(+) currents of activated glial cells surrounding ischemic infarcts are investigated using acutely dissociated cells from the periinfarct area after permanent middle cerebral artery occlusion in rats. Inwardly rectifying K(+) currents (K(IR)) were markedly reduced in cells neighboring infarcts with maximal alteration at day 3 after infarct followed by a partial recovery. This reduction of glial K(IR) currents may contribute to the functional disturbances in the periinfarct area.

Animals↗
PubMed2000

Differential regulation of microglial keratan sulfate immunoreactivity by proinflammatory cytokines and colony-stimulating factors.

Resident microglia of the rat CNS express a unique type of keratan sulfate immunoreactivity (KS-IR) that is lacking on peripheral monocytes/macrophages and associated with a so far unknown proteoglycan core protein. Microglial KS-IR is downregulated during T-cell-mediated autoimmune inflammation but largely preserved in degenerative lesion paradigms. This study addresses the role of cytokines and colony-stimulating factors in the regulation of microglial KS-IR. In vitro, ramified microglia in coculture with astrocytes, but not isolated microglia, constitutively expressed KS-IR under control conditions. In both culture paradigms, KS-IR was increased significantly by macrophage- (M-CSF) and granulocyte/macrophage colony-stimulating factors (GM-CSF), as well as tumor necrosis factor-alpha (TNF-alpha). By contrast, the Th1 cytokine interferon-gamma (IFN-gamma) downregulated KS-IR, both when applied alone or in combination with either GM-CSF, M-CSF, or TNF-alpha. In vivo, the intracerebroventricular administration of IFN-gamma, but not TNF-alpha, to healthy rats led to an almost complete disappearance of KS-IR from ramified brain microglia. Our data suggest that the expression of microglial KS-IR is under dominant negative control by the Th1 cell cytokine IFN-gamma and represent the first evidence of cytokine-dependent proteoglycan regulation in the CNS.

Animals↗
PubMed2000

Cytokines in CNS disorders: neurotoxicity versus neuroprotection.

Cytokines orchestrate T cell-mediated immune responses. In experimental autoimmune encephalomyelitis (EAE) the proinflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-12 and IL-18 are critically involved in the initiation and amplification of the local immune response in the CNS which is counter-balanced by upregulation of antiinflammatory cytokines such as IL-10. The predicted function of individual cytokines during EAE has recently been challenged by transgenic animal studies and neutralization experiments. Cytokine induction is not restricted to autoimmunity in the nervous system. Cytokines are involved in nerve regeneration and induced in focal cerebral ischemia both at the site of infarction and in remote nonischemic brain regions. In cerebral ischemia TNF-alpha and IL-1beta probably have dual functions: In concert with upregulation of inducible NO synthase (iNOS) they exert neurotoxicity while in the absence of iNOS, TNF-alpha and IL-1beta may contribute to neuroprotection and plasticity. The interplay between glial cells, infiltrating leukocytes and induced cytokines leading to CNS pathology is complex and incompletely understood. Further assessment of the functional contribution of cytokines critically depends on the elucidation of downstream secondary signaling mechanisms.

Animals↗
PubMed2000

[Unstable carotid stenosis--an inflammatory disease?].

Arterioarterial thromboembolism from extracranial internal carotid artery (ICA) stenosis is an important pathogenic mechanism of ischemic stroke. However, even a high-grade ICA stenosis carries a greatly variable annual risk of stroke, as high as 13% following a recent occurrence of transient or minor cerebral ischemia or as low as 1-2% in clinically asymptomatic patients. There is increasing evidence that inflammatory processes play a central role in atherosclerosis and particularly in plaque destabilization converting chronic atherosclerosis into an acute neurological disorder. In thromboendarterectomy specimens from patients with high-grade ICA stenoses, the extent of inflammatory infiltration and the expression of matrixmetalloproteinase-9 correlated to clinical and ultrasonic features of plaque destabilization such as cerebral microembolism. Inflammation might become a new therapeutic target in symptomatic carotid artery disease.

Carotid Artery, Internal↗
PubMed1999

The role of microglia and macrophages in the pathophysiology of the CNS.

Microglia are a major ghal component of the central nervous system (CNS) and are extremely sessile. Only a subtype, the perivascular microglia, are regularly replaced from the bone marrow in adult animals. Microglia respond to virtually any, even minor pathological events in the CNS. In most pathological settings microglia are aided by infiltrating hematogenous macrophages. Upon activation microglia and macrophages share most phenotypical markers and can exert similar effector functions. After transection of a CNS fibre tract microglia are insufficiently activated and hematogenous macrophages do not significantly enter the degenerating nerve stump. Thereby myelin debris that contains neurite outgrowth inhibiting activity persists for long time. This is in sharp contrast to the peripheral nervous system in which hematogenous macrophages are rapidly recruited in response to axotomy and clear myelin debris allowing regrowth of axons from the proximal stump. However, CNS lesion paradigms with breakdown of the blood-brain barrier such as cerebral ischemia, brain abscesses and stab wounds elicit prompt microglial activation, macrophage recruitment and debris clearance. There is increasing evidence that microglia play an active part in degenerative CNS diseases. In Alzheimer's disease activated microglia appear to be involved in plaque formation. In experimental globoid cell dystrophy T-cell independent induction of major histocompatibility complex class II molecules on microglia accelerates demyelination. In autoimmune diseases microglia probably have dual functions. Microglia present antigen to infiltrating T cells and exert effector functions thereby locally augmenting immune responses. On the other hand, microglia have the capacity to downregulate T cell responses. In the human acquired immunodeficiency syndrome (AIDS) virus infected macrophages probably introduce the virus to the CNS and in concert with microglia are involved in the pathophysiology of the AIDS dementia complex.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex.

This study examined microglial responses after photochemically induced focal ischemia of the rat cortex. Microglial activation exceeded by far the area of the ischemic lesion. Based on morphological criteria and expression of immunomolecules three distinct patterns could be distinguished. (1) In the infarct core and the border zone microglia transformed into phagocytes and removed debris with the aid of hematogeneous macrophages. Exclusively in this area a subpopulation of CD8+ microglia/mnacrophages was present. (2) In secondarily degenerating fibre tracts and nuclei with retrograde neuronal loss, microglia were activated with a delay of days and showed increased expression of complement receptor 3, major histocompatibility complex class II and CD4 molecules, but only low phagocytic activity. (3) In remote ipsilateral cortex devoid of neuronal damage, microglia transiently responded by increased complement receptor 3, but not by major histocompatibility complex class II and CD4 expression. Furthermore, the total number of microglia had increased. This remote response could partly be blocked by dizocilpine maleate, a non-competitive N-methyl-D-aspartate receptor antagonist, implicating a functional role of spreading depression. Taken together, our findings point to a tight and differential regulation of microglial responses in the infarct core, degenerating fibre tracts and remote brain regions without neuronal loss.

Animals↗
PubMed1999

Nerve injury, axonal degeneration and neural regeneration: basic insights.

Axotomy or crush of a peripheral nerve leads to degeneration of the distal nerve stump referred to as Wallerian degeneration (WD). During WD a microenvironment is created that allows successful regrowth of nerve fibres from the proximal nerve segment. Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. They finally aline in tubes (Büngner bands) and express surface molecules that guide regenerating fibres. Hematogenous macrophages are rapidly recruited to the distal stump and remove the vast majority of myelin debris. Molecular changes in the distal stump include upregulation of neurotrophins, neural cell adhesion molecules, cytokines and other soluble factors and their corresponding receptors. Axonal injury not only induces muscle weakness and loss of sensation but also leads to adaptive responses and neuropathic pain. Regrowth of nerve fibres occurs with high specificity with formerly motor fibres preferentially reinnervating muscle. This involves recognition molecules of the L2/HNK-1 family. Nerve regeneration occurs at a rate of 3-4 mm/day after crush and 2-3 mm/day after sectioning a nerve. Nerve regeneration can be fostered pharmacologically. Upon reestablishment of axonal contact Schwann cells remyelinate nerve sprouts and downregulate surface molecules characteristic for precursor/premyelinating or nonmyelinating Schwann cells. At present it is unclear whether axonal regeneration after nerve injury is impeded in neuropathies.

Animals↗
PubMed1998

Differential induction of interleukin-12, interleukin-18, and interleukin-1beta converting enzyme mRNA in experimental autoimmune encephalomyelitis of the Lewis rat.

Experimental autoimmune encephalomyelitis (EAE) is a model of autoimmune central nervous system (CNS) disease that is mediated by autoreactive Th1 cells secreting the proinflammatory cytokine interferon (IFN)-gamma. Interleukin (IL)-12 in its heterodimeric p35/p40 isoform and the recently described cytokine IL-18 potently induce T cell production of IFN-gamma. Interleukin-1beta converting enzyme (ICE) is required to convert IL-18 precursor protein into its biologically active mature form. In this study, we used semiquantitative reverse transciptase-polymerase chain reaction to determine steady state levels of IL-12, IL-18, and ICE mRNA in the spinal cord of Lewis rats at different stages of EAE. In control rats, we found significant IL-18, ICE, and IL-12p35, but not IL-12p40 mRNA expression. IL-18 mRNA increased during the acute stage of EAE together with a marked induction of ICE mRNA. IL-12p35 mRNA levels did not change significantly throughout the course of EAE. Surprisingly, the peak expression of IL-12p40 mRNA was delayed by several days relative to the peak of T cell infiltration and IFN-gamma mRNA synthesis. Our data implicate the IL-18/ICE pathway in the amplification of Th1-mediated immune responses in the CNS but suggest a different, so far undefined role of endogenous IL-12 in the late effector phase of EAE.

Animals↗
PubMed1998

TNF alpha induces a protein kinase C-dependent reduction in astroglial K+ conductance.

Incubation of cultured cortical astrocytes with tumor necrosis factor alpha (TNF alpha) led to a marked reduction of membrane potential. Here we report that this depolarization depends on activation of protein kinase C (PKC), since it could be blocked by the PKC antagonists staurosporine and H7 and it could be mimicked by direct activation of PKC using the phorbol ester phorbol 12-myristate 13 acetate (PMA). Analyses of whole cell currents revealed a reduction of inwardly rectifying K+ currents whereas K+ outward currents were not affected. We conclude that TNF alpha induces changes of basic electrophysiological properties of astrocytes which are similar to those induced by proliferation or an in vitro model of traumatic injury.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Sequential expression of mRNA for proinflammatory cytokines and interleukin-10 in the rat peripheral nervous system: comparison between immune-mediated demyelination and Wallerian degeneration.

This study examined the time course of mRNA levels of the proinflammatory cytokines interferon-gamma (IFNgamma), interleukin-1beta (IL1beta), interleukin-12 (IL12; p40 subunit), and the immunosuppressant interleukin-10 (IL10) by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) in rats with actively induced experimental autoimmune neuritis (EAN) and in distal stumps of crushed sciatic nerves undergoing Wallerian degeneration. In EAN IFNgamma- and IL1beta-mRNA peaked at the onset and acute phase of clinical disease. IL12p40-mRNA was upregulated later than IFNgamma-mRNA in the late acute phase from days 15 to 21. IL10-mRNA appeared concomitantly with the proinflammatory cytokines at day 11, but persisted at high levels into the clinical recovery phase. After nerve crush both IL1beta- and IL10-mRNA were rapidly upregulated in the distal stump at day 1 and slowly declined over the next 2 weeks. Significant levels of mRNA for IFNgamma could be found at days 4 and 7, whereas IL12p40-mRNA showed a biphasic induction. We provide evidence for a concomitant induction of pro- and anti-inflammatory cytokines in EAN. Moreover, the rapid upregulation in Wallerian degeneration suggests a more general role of cytokines in the biology of the peripheral nerve.

Animals↗
PubMed1998

Major histocompatibility complex class II expression and macrophage responses in genetically proven Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies.

This study examined major histocompatibility complex (MHC) class II expression and macrophage infiltration in sural nerve biopsies from patients with genetically proven Charcot-Marie-Tooth (CMT) 1A and 1B and hereditary neuropathy with liability to pressure palsies (HNPP) by immunocytochemistry. In both young and older patients with duplication of the PMP22 gene, MHC class II expression was consistently up-regulated and not closely related to the extent of macrophage infiltration. On the other hand, MHC class II expression was more variable in CMT1A and CMT1B caused by point mutations and in HNPP. The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP. We conclude that MHC class II up-regulation is a common feature in hereditary neuropathies. As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology.

Adolescent↗
PubMed1998

A new correlation-based fuzzy logic clustering algorithm for fMRI.

Fuzzy logic clustering algorithms are a new class of processing strategies for functional MRI (fMRI). In this study, the ability of such methods to detect brain activation on application of a stimulus task is demonstrated. An optimization of the selected algorithm with regard to different parameters is proposed. These parameters include (a) those defining the pre-processing procedure of the data set; (b) the definition of the distance between two time courses, considered as p-dimensional vectors, where p is the number of sequential images in the fMRI data set; and (c) the number of clusters to be considered. Based on the assumption that such a clustering algorithm should cluster the pixel time courses according to their similarity and not their proximity (in terms of distance), cross-correlation-based distances are defined. A clear mathematical description of the algorithm is proposed, and its convergence is proven when similarity measures are used instead of conventional Euclidean distance. The differences between the membership function given by the algorithm and the probability are clearly exposed. The algorithm was tested on artificial data sets, as well as on data sets from six volunteers undergoing stimulation of the primary visual cortex. The fMRI maps provided by the fuzzy logic algorithm are compared to those achieved by the well established cross-correlation technique.

Algorithms↗
PubMed1998

Inflammation and glial responses in ischemic brain lesions.

Focal cerebral ischemia elicits a strong inflammatory response involving early recruitment of granulocytes and delayed infiltration of ischemic areas and the boundary zones by T cells and macrophages. Infiltration of hematogenous leukocytes is facilitated by an upregulation of the cellular adhesion molecules P-selectin, intercellular adhesion molecule-1 and vascular adhesion molecule-1 on endothelial cells. Blocking of the leukocyte/endothelial cell adhesion process significantly reduces stroke volume after transient, but not permanent middle cerebral artery occlusion. In the infarct region microglia are activated within hours and within days transform into phagocytes. Astrocytes upregulate intermediate filaments, synthesize neurotrophins and form glial scars. Local microglia and infiltrating macrophages demarcate infarcts and rapidly remove debris. Remote from the lesion no cellular infiltration occurs, but astroglia and microglia are transiently activated. Astrocytic activation is induced by spreading depression. In focal ischemia neurons die acutely by necrosis and in a delayed fashion by programmed cell death, apoptosis. Proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta are upregulated within hours in ischemic brain lesions. Either directly or via induction of neurotoxic mediators such as nitric oxide, cytokines may contribute to infarct progression in the post-ischemic period. On the other hand, inflammation is tightly linked with rapid removal of debris and repair processes. At present it is unclear whether detrimental effects of inflammation outweigh neuroprotective mechanisms or vice versa. In global ischemia inflammatory responses are limited, but micro- and astroglia are also strongly activated. Glial responses significantly differ between brain regions with selective neuronal death and neighbouring areas that are more resistent to ischemic damage.

Animals↗
PubMed1998

Focal ischaemia of the rat brain elicits an unusual inflammatory response: early appearance of CD8+ macrophages/microglia.

Cerebral ischaemia leads to profound glial activation and leukocyte infiltration into the infarct area. In this study, we provide evidence for a dual macrophage response in focal ischaemic lesions of the rat brain. We show that a considerable proportion of macrophages in the ischaemic lesions express the CD8alphabeta heterodimer to date only described on CD8+ T cells. As known from other lesion paradigms, CD4+ macrophages were also present. Interestingly, CD8- and CD4-expressing macrophages formed two non-overlapping subpopulations. CD8+ macrophages reached their maximum during the first week with pronounced downregulation thereafter whereas CD4+ cells persisted at high levels into the second week. In contrast to cerebral ischaemia, macrophages in the spleen and in Wallerian degeneration after optic nerve axotomy expressed CD4, but not CD8. In experimental autoimmune encephalomyelitis, CD8 was mainly associated with T cells and very weakly detectable on some ramified cells resembling activated microglia. In conclusion, we show that cerebral ischaemia triggers an unusual inflammatory response characterized by the appearance of CD8+/CD4- macrophages that might exert specific functions in the pathogenesis of ischaemic brain damage.

Animals↗
PubMed1998

Nerve injury and regeneration: basic insights and therapeutic interventions.

Recent observations have provided new insight into neuronal responses to axotomy, signalling of the Schwann cell switch from 'operating' to 'proliferation' mode and temporal molecular changes in the responsiveness of Schwann cells to neuronal signals, as well as into the role of macrophages in Wallerian degeneration, nerve repair and neuropathic pain. Furthermore, promising therapeutic interventions have been developed to promote axon regeneration and to attenuate axotomy-induced neuronal cell death by means of pharmacological treatment or application of neurotrophic proteins using various strategies and routes of delivery.

Animals↗
PubMed1998

Differential regulation of Bax, Bcl-2, and Bcl-X proteins in focal cortical ischemia in the rat.

Focal ischemia in the parietal cortex of the rat results in massive neuronal death in the infarct zone and penumbra between 12 hours and 6 days after photothrombosis. To examine a possible role of Bcl-2 family proteins in this process of cell death, we investigated their expression by immunoblot assays and immunocytochemistry, and correlated expression patterns with TUNEL as well as morphological signs indicative of apoptosis. In the center of the lesion Bax immunostaining was increased in many degenerating neurons between 4 hours and 3 days after the induction of photothrombosis. At all time points examined, Bcl-2 and Bcl-X protein levels were markedly reduced in injured neurons as compared to the unlesioned side. At the border of the ischemic lesion, two areas were distinguished: 1 - 2 days after induction of photothrombosis, pyknotic cells located immediately adjacent to the lesion core displayed nuclear Bcl-X and Bax immunoreactivity. In contrast, large, morphologically intact neurons located more towards the healthy brain parenchyma displayed an increase in cytoplasmic Bcl-2 and Bcl-X proteins. Double staining for each of the Bcl-2 family proteins and TUNEL revealed that DNA strand breaks and nuclear fragmentation seen in cells located in the lesion core were often associated with increased levels of Bax, but not with elevated Bcl-2 or Bcl-X protein levels, suggesting a role for Bax in the induction of apoptotic death in these cells. The upregulation of Bcl-2 and Bcl-X expression in surviving neurons close to the penumbra might reflect an active survival mechanism that protects these neurons from cell death following a sublethal insult.

Animals↗
PubMed1998

Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization.

BACKGROUND AND PURPOSE: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS: Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS: The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS: Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Adult↗