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L Mucke

Publications and source records attributed to L Mucke.

68 records · Page 4Linked to original sources
PubMed1993

Expression of cathepsin G-like and alpha 1-antichymotrypsin-like proteins in reactive astrocytes.

The central nervous system (CNS) of many different species responds to diverse neurologic injuries with an activation of astrocytes. Yet, the exact function of this reactive astrocytosis is unknown. In this report, mouse astrocytes were activated in vivo by focal penetrating brain injury. Reactive astrocytes were stained with antibodies raised against the serine protease cathepsin G (cat.G), the serine protease inhibitor alpha 1-antichymotrypsin (ACT), or the astrocytic marker glial fibrillary acidic protein (GFAP). Reactive astrocytes expressing both cat.G-like and ACT-like antigens were found around cerebral wound margins between 18 h and 13 days after neural lesions. The injury-induced immunostaining was unaltered by 900 rads of total body irradiation, suggesting that the astroglial reaction was relatively independent of bone marrow-derived cells. The in vivo immunostaining was complemented with biochemical assays on cultured primary astrocytes. A synthetic peptide was used as a substrate in combination with specific inhibitors to identify a proteolytic activity within astroglial lysates and culture supernatants that closely resembles cat.G. This activity increased substantially upon stimulation of astrocytes with dibutyryl cyclic AMP and was neutralized by antibodies raised against cat.G. In a separate report, it was shown that astrocytes also contain an ACT-like inhibitory activity. The production of ACT- and cat.G-like antigens and activities by activated astrocytes should allow these cells to participate in a number of important biologic processes. Many of these processes may benefit the CNS by assisting in early wound repair. However, astroglial proteases and their inhibitors could also contribute to the pathogenesis of certain neurologic diseases.

Amino Acid Sequence↗
PubMed1993

Molecular profile of reactive astrocytes--implications for their role in neurologic disease.

The central nervous system responds to diverse neurologic injuries with a vigorous activation of astrocytes. While this phenomenon is found in many different species, its function is obscure. Understanding the molecular profile characteristic of reactive astrocytes should help define their function. The purpose of this review is to provide a summary of molecules whose levels of expression differentiate activated from resting astrocytes and to use the molecular profile of reactive astrocytes as the basis for speculations on the functions of these cells. At present, reactive astrocytosis is defined primarily as an increase in the number and size of cells expressing glial fibrillary acidic protein. In vivo, this increase in glial fibrillary acidic protein-positive cells reflects predominantly phenotypic changes of resident astroglia rather than migration or proliferation of such cells. Upon activation, astrocytes upmodulate the expression of a large number of molecules. From this molecular profile it becomes apparent that reactive astrocytes may benefit the injured nervous system by participating in diverse biological processes. For example, upregulation of proteases and protease inhibitors could help remodel the extracellular matrix, regulate the concentration of different proteins in the neuropil and clear up debris from degenerating cells. Cytokines are key mediators of immunity and inflammation and could play a critical role in the regulation of the blood-central nervous system interface. Neurotrophic factors, transporter molecules and enzymes involved in the metabolism of excitotoxic amino acids or in the antioxidant pathway may help protect neurons and other brain cells by controlling neurotoxin levels and contributing to homeostasis within the central nervous system. Therefore, an impairment of astroglial performance has the potential to exacerbate neuronal dysfunction. Based on the synopsis of studies presented, a number of issues become apparent that deserve a more extensive analysis. Among them are the relative contribution of microglia and astrocytes to early wound repair, the characterization of astroglial subpopulations, the specificity of the astroglial response in different diseases as well as the analysis of reactive astrocytes with techniques that can resolve fast physiologic processes. Differences between reactive astrocytes in vivo and primary astrocytes in culture are discussed and underline the need for the development and exploitation of models that will allow the analysis of reactive astrocytes in the intact organism.

Antibody Formation↗
PubMed1993

Astrocytes in infectious and immune-mediated diseases of the central nervous system.

The central nervous system (CNS) can be invaded and damaged by a variety of microbes. The host response to such injury involves CNS cells, and in many cases hematogenous cells also. Recent experiments indicate that astrocytes, macroglial resident cells of the CNS, play key roles in this process. The astroglial production of trophic factors and elimination of neurotoxins are likely to fulfill important protective and reparative functions during CNS infection. In addition, astrocytes could, in concert with microglial cells, regulate the recruitment and activity of infiltrating hematogenous cells through their expression of cytokines, proteases, protease inhibitors, adhesion molecules, and extracellular matrix components. Although previous experiments suggested that astrocytes might initiate inflammatory demyelinating disease by presenting CNS antigens to autoreactive immune cells, current evidence points against such a detrimental activity. In view of the generally beneficial role of astrocytes, impairments of astroglial function by microbes or host-derived factors have the potential to contribute to neurologic disease. Diseases in which this pathogenetic process may be relevant include HIV-1-associated cognitive/motor complex and spongiform encephalopathies.

Animals↗
PubMed1992

The expression of major histocompatibility complex (MHC) class I antigens in the brain differs markedly in acute and persistent infections with lymphocytic choriomeningitis virus (LCMV).

Intracranial inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) induces a fatal neurologic illness. In this disease a marked increase in MHC class I expression was found, closely associated with viral antigens and inflammatory infiltrates, in meninges, choroid plexus and ventricular ependyma but not within the brain parenchyma. Immunosuppression prevented MHC induction. Mice inoculated at birth had persistent infections, with LCMV antigens found primarily in neurons, but no inflammatory cells or focal increase in MHC class I. Failure of infected neurons to express MHC class I allows them to escape destruction by cytotoxic T cells (CTL) but may increase their susceptibility to be persistently infected by non-lytic viruses.

Acute Disease↗
PubMed1991

Viral persistence in neurons explained by lack of major histocompatibility class I expression.

Viruses frequently persist in neurons, suggesting that these cells can evade immune surveillance. In a mouse model, 5 x 10(6) cytotoxic T lymphocytes (CTLs), specific for lymphocytic choriomeningitis virus (LCMV), did not lyse infected neurons or cause immunopathologic injury. In contrast, intracerebral injection of less than 10(3) CTL caused disease and death when viral antigens were expressed on leptomeningeal and choroid plexus cells of the nervous system. The neuronal cell line OBL21 expresses little or no major histocompatibility (MHC) class I surface glycoproteins and when infected with LCMV, resisted lysis by virus-specific CTLs. Expression of MHC heavy chain messenger RNA was limited, but beta 2-microglobulin messenger RNA and protein was made normally. OBL21 cells were made sensitive to CTL lysis by transfection with a fusion gene encoding another MHC class I molecule. Hence, neuronal cells probably evade immune surveillance by failing to express MHC class I molecules.

Acute Disease↗
PubMed1991

Rapid activation of astrocyte-specific expression of GFAP-lacZ transgene by focal injury.

Astrocytes form a key cellular component of the central nervous system. They respond vigorously to diverse neurologic insults by undergoing hypertrophy and increasing expression of the glial fibrillary acidic protein (GFAP) gene, but their functions are largely unknown. To analyze astrocytes in vivo we constructed a transgenic vector from GFAP gene sequences and monitored its efficiency by fusing it to lacZ. Injection of the GFAP-lacZ hybrid gene into the germline of mice yielded six different lines of transgenic mice. In all lines the expression of lacZ was astrocyte-specific. In unmanipulated transgenic animals beta-galactosidase activity was much more prominent in astrocytes of the hippocampal formation, selected white matter tracts, and glial limitans than in astrocytes of other areas. This pattern of expression illustrates the physiologic heterogeneity of astrocytes and probably reflects differences in functional demands placed on these cells in different brain regions. Upmodulation of transgene expression was used to determine the time frame within which astroglial activation and increased GFAP gene expression occur following a neurologic insult. Induction of GFAP-lacZ expression was detectable within 1 hour after focal mechanical trauma. This demonstrates that the response of astrocytes to neurologic injury is very rapid and implies that these cells could fulfill important early functions in wound healing within the central nervous system.

Animals↗
PubMed1990

Identification of a functional glucocorticoid response element in the phenylethanolamine N-methyltransferase promoter using fusion genes introduced into chromaffin cells in primary culture.

The rat gene encoding phenylethanolamine N-methyltransferase (PNMT) was cloned and a consensus sequence for a glucocorticoid response element (GRE) was found at -513 bp, 5' to the transcriptional start site. In order to define the function of this element, fusion genes containing the PNMT promoter and a chloramphenicol acetyltransferase (CAT) reporter gene were constructed. These constructs did not express after transfection into any of 7 continuous cell lines, none of which endogenously produce PNMT. A system for transfecting chromaffin cells in primary culture was therefore devised using constructs containing 200 bp of the proenkephalin (ENK) promoter, whose expression characteristics are well known. pENK beta GAL-1, containing the ENK promoter with a lac Z reporter, was introduced into these cells and beta-galactosidase activity was visualized in situ. Approximately 90% of cells transfected were chromaffin; transfection efficiency was 5%. High levels of CAT activity were measured in chromaffin cells transfected with pENKAT12, possessing a CAT reporter. In contrast to tumor cell lines, pENKAT12 induction in these cells by forskolin and phorbol esters did not require a phosphodiesterase inhibitor. In this chromaffin system, both basal and regulated expression of the PNMT fusion genes were detected. Dexamethasone (dex) induced expression of pPNMT3000 and pPNMT900, containing the putative GRE and 3000 bp or 863 bp of PNMT promoter sequence, 4- to 10-fold. Expression of pPNMT300 and pPNMT100, which lack the GRE and contain 273 bp or 99 bp of PNMT promoter sequence, was unaffected by dex. Addition of the PNMT region spanning -490 to -863 bp conferred full dex responsiveness to a thymidine kinase promoter. Deletion of the putative GRE sequence by site-directed mutagenesis abolished the dex response. These data identify the sequence at -513 bp in the rat PNMT gene as a functional, positively acting GRE. Primary cultures of bovine chromaffin cells provide a biologically relevant expression system for transcriptional studies of catecholamine genes and their related neuropeptides.

Animals↗
PubMed1988

Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy.

Two human immunodeficiency virus seropositive patients with progressive multifocal leukoencephalopathy (PML) exhibited a dramatic though incomplete recovery of neurologic function and have survived for more than 30 months since the onset of symptoms. PML was the initial manifestation of the acquired immune deficiency syndrome (AIDS) in both patients, though other opportunistic infections have subsequently supervened in one. Brain tissue from both patients obtained by stereotactic biopsy showed the typical features of PML, but was also characterized by an unusually prominent inflammatory response. Neurologic improvement did not appear to correlate with clinical or laboratory measurements of immunologic improvement. One patient continued to display neurologic recovery despite the development of other opportunistic infections. Though atypical, PML in AIDS may be associated with prolonged survival.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Clinical management of neuropathic pain.

Neuropathic pain is often a significant source of protracted suffering, seriously impairing efforts at functional rehabilitation of affected patients. The assessment and treatment of pain symptoms in patients with disease affecting peripheral and central somatosensory pathways is therefore an important problem in clinical management and rehabilitation of patients with neurologic disease.

Animals↗
PubMed1986

Connections of the anterior ectosylvian visual area (AEV).

We have previously described a visual area situated in the cortex surrounding the deep infolding of the anterior ectosylvian sulcus of the cat (Mucke et al. 1982). Using orthograde and retrograde transport methods we now report anatomical evidence that this anterior ectosylvian visual area (AEV) is connected with a substantial number of both cortical and subcortical regions. The connections between AEV and other cortical areas are reciprocal and, at least in part, topographically organized: the rostral AEV is connected with the bottom region of the presylvian sulcus, the lower bank of the cruciate sulcus, the rostral part of the ventral bank of the splenial sulcus, the rostral portion of the lateral suprasylvian visual area (LS) and the lateral bank of the posterior rhinal sulcus; the caudal AEV is connected with the bottom region of the presylvian sulcus, the caudal part of LS, the ventral part of area 20 and the lateral bank of the posterior rhinal sulcus. Subcortically, AEV has reciprocal connections with the ventral medial thalamic nucleus (VM), with the medial part of the lateralis posterior nucleus (LPm), as well as with the lateralis medialis-suprageniculate nuclear (LM-Sg) complex. These connections are also topographically organized with more rostral parts of AEV being related to more ventral portions of the LPm and LM-Sg complex. AEV also projects to the caudate nucleus, the putamen, the lateral amygdaloid nucleus, the superior colliculus, and the pontine nuclei. It is concluded that AEV is a visual association area which functionally relates the visual with both the motor and the limbic system and that it might play a role in the animal's orienting and alerting behavior.

Afferent Pathways↗
PubMed1982

Physiologic and anatomic investigation of a visual cortical area situated in the ventral bank of the anterior ectosylvian sulcus of the cat.

In this paper a cortical area is described that covers approximately the posterior two-thirds of the ventral bank of the anterior ectosylvian sulcus of the cat and is called anterior ectosylvian visual area (AEV). In cats anesthetized with a combination of N2O and barbiturate we explored this area by recording extracellularly the responses of AEV neurons to visual and electric stimulation as well as by injecting HRP into physiologically verified points. AEV neurons were found to be highly sensitive to small light stimuli moving rapidly in a particular direction through their large receptive fields. The properties of 74 neurons were quantitatively analyzed. Increasing the length of the stimulus within the receptive field to more than 2 deg strongly inhibited the responses, whereas increasing the speed of the stimulus movement up to 72-120 deg/s enhanced the neuronal responsiveness. Although the majority of neurons responded to a wide range of possible directions, one clearly preferred direction could usually be found for each neuron. There was predominance of preferred directions toward the contralateral hemifield. Anatomic and electrophysiologic connectivity studies showed that AEV receives its main afferent inputs from the lateral suprasylvian visual area (LS) and from the tecto-pulvinar complex. Although these studies suggested some topographical organization within the projection from LS to AEV, the large receptive fields in AEV, the great majority of which included the central area, did not reveal a clear retinotopic order. It is concluded that AEV is a specific visual area and that functionally the extrageniculate inputs predominate.

Animals↗