Cerebral angiography complications link cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy to familial hemiplegic migraine.
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Brain Diseases↗
Biomedical subjects
M Weller
Publications and source records attributed to M Weller.
[New therapeutic possibilities with low-affinity NMDA receptor antagonists].
Glutamate receptor antagonists with selective action at the N-methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson's disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not.
Aged↗
Apoptotic cell death in proliferative vitreoretinopathy.
Apoptosis is a selective event of physiological cell deletion that plays a crucial role in the development of numerous tissues, including the retina. In this paper we report the occurrence of apoptosis in epiretinal membranes derived from patients with proliferative vitreoretinopathy (PVR). Detection of apoptosis was performed by an in situ DNA-end labeling technique using terminal transferase-mediated deoxyuridine triphosphate (dUTP) incorporation. Apoptotic nuclei exhibiting chromatin condensation and fragmentation were also identified by acridine orange fluorescence. Apoptosis was detected in varying numbers of cells. The typical appearance of apoptotic nuclei, including nuclear chromatin condensation, was detected scattered inhomogeneously throughout the epiretinal membranes, in clusters, or even in single cells. Induction of apoptosis in human retinal pigment epithelial (RPE) cells by daunomycin could be demonstrated by in situ DNA end labeling and by quantitative determination of cytoplasmatic histone-associated DNA fragments using a photometric enzyme immunoassay. Since apoptosis has been shown to be an important factor in the growth control of various untransformed and neoplastic cell populations, the pharmacological induction of apoptosis in epiretinal membranes could result in a new approach toward inhibiting cellular proliferation in PVR.
Adult↗
CD 95 expression in traumatic proliferative vitreoretinopathy: a target for the induction of apoptosis.
Apoptotic cell death is a central mechanism underlying growth regulation in normal and pathologic neoplastic and nonneoplastic tissue formation. Apoptosis has also been detected in traction membranes of patients with proliferative vitreoretinopathy (PVR). Herein we report that CD 95 (Fas/APO-1), the cell-surface receptor for a potent proapoptotic cytokine, the CD 95 ligand, is expressed in traction membranes of patients with traumatic PVR. Retinal pigment epithelial (RPE) cells, which are thought to contribute to traction membrane formation, express CD 95 in vitro. However, these cells are resistant to CD 95 antibody-induced apoptosis, presumably because they synthesize cytoprotective proteins, which interfere with the CD 95-dependent killing cascade. Coexposure to inhibitors of RNA or protein synthesis sensitizes human RPE cells for CD 95-mediated apoptosis. In contrast, these agents have little effect on the resistance of these cells to tumor necrosis factor-alpha(TNF-alpha). Pre-exposure to TNF-alpha augments CD 95-mediated killing but not its own toxicity in the presence of inhibitors of RNA and protein synthesis. Preexposure to cycloheximide does not abrogate CD 95-mediated apoptosis, suggesting that labile, short-lived proteins do not mediate the cytotoxic effects of CD 95 antibodies. Taken together, our data indicate that immune-mediated CD 95-dependent killing of proliferating cells in vitreoretinal traction membranes might occur in vivo and could possibly be enhanced using novel approaches of immunopharmacotherapy.
Adolescent↗
Apoptotic cell death in the cerebellum of mutant weaver and lurcher mice.
Apoptosis in the central nervous system of mutant weave (wv) and lurcher (lc) mice was studied using in situ DNA end-labeling. The number of apoptotic cells in the external granule cell layer of weaver (wv/+) mice at postnatal day 9 was increased six- to eight-fold compared to (+/+) littermates. Purkinje cells and Bergmann glia cells were not affected. No labeled cells were found in the substantia nigra. In lurcher (lc/+) mice, labeled nuclei of large cells were found in the Purkinje cell layer, suggesting that Purkinje cells of mutant lurcher mice undergo apoptosis. Apoptotic granule cell nuclei were found in the internal granule cell layer. In contrast to weaver (wv/+) mice, the number of apoptotic cells in the external granule cell layer was not increased. Apoptosis appears to be the common pathway of cell death in the degenerative processes induced by the weaver and the lurcher gene, respectively. These mutant mice offer the opportunity to study the mechanisms that underlie inappropriate apoptotic cell death in vivo.
Animals↗
CD95 (Fas/APO-1) antibody-mediated apoptosis of human retinal pigment epithelial cells.
CD95 (Fas/APO-1) is a cytokine receptor protein that signals apoptosis. Here we report that human retinal pigment epithelial cells express CD95 but are rather resistant to agonistic CD95 antibodies. Resistance to CD95 antibodies is overcome by preexposure to the cytokines, tumor necrosis factor-alpha or interferon-gamma, or by coexposure to CD95 antibodies and inhibitors of RNA or protein synthesis. The cells are resistant to tumor necrosis factor-alpha even in the presence of cycloheximide and only moderately sensitized to tumor necrosis factor-alpha-mediated toxicity by coexposure to actinomycin D. CD95-mediated apoptosis is inhibited by dexamethasone both after cytokine sensitization and upon coexposure to CD95 antibodies and actinomycin D or cycloheximide. Induction of apoptosis via CD95 may be involved in the regulation of retinal pigment epithelial proliferation at the vitreoretinal interface.
Antigens, Surface↗
Fas/APO-1 gene transfer for human malignant glioma.
Human malignant glioma cells are susceptible to apoptosis induced by antibodies to Fas/APO-1, a cytokine receptor protein of the nerve growth factor/tumor necrosis factor receptor superfamily. Here we show that a critical level of cell surface expression of Fas/APO-1 is a prerequisite for induction of glioma cell apoptosis via Fas/APO-1. Although Fas/APO-1 mRNA was expressed in three Fas/APO-1 antibody-resistant glioma cell lines, these cells expressed either little Fas/APO-1 protein (LN-319 and LN-405) or an abnormal Fas/APO-1 protein that was not translocated to the cell membrane and therefore functionally inactive (LN-308). Although all glioma cell lines expressed mRNA for Fas/APO-1-delta TM, a soluble form of Fas/APO-1 lacking the transmembrane domain, none of the cell lines released detectable amounts of soluble Fas/APO-1, a potential endogenous antagonist of Fas/APO-1-mediated glioma cell apoptosis. Stable transfection of three resistant glioma cell lines with a human Fas/APO-1 cDNA expression vector dramatically enhanced cell surface expression of Fas/APO-1 and induced susceptibility to Fas/APO-1 antibody-mediated apoptosis. These data indicate that malignant glioma cells, unlike other tumor cells, uniformly harbor the intracellular cascade required for Fas/APO-1-mediated apoptosis. Low level of Fas/APO-1 expression results from inefficient transcription and translation of the Fas/APO-1 gene or the synthesis of mutant Fas/APO-1 proteins. gamma-Interferon, tumor necrosis factor-alpha, and interleukin 1 beta augmented Fas/APO-1-mediated apoptosis of Fas/APO-1-transfected glioma cells by acting on the subcellular suicidal cascade triggered by Fas/APO-1 activation. Dexamethasone attenuated Fas/APO-1 antibody-induced apoptosis, not only of constitutively Fas/APO-1-positive glioma cells, but also of Fas/APO-1-transfected glioma cells. The antiapoptotic effect of dexamethasone could be overcome by preexposure of the glioma cells to gamma-interferon or by coexposure to Fas/APO-1 antibodies and cycloheximide. Thus, Fas/APO-1 gene transfer and combined immunotherapy using Fas/APO-1 antibodies and cytokines may overcome Fas/APO-1 antibody resistance of Fas/APO-1-negative human malignant glioma cells, which may represent subpopulations within single gliomas or form a separate subgroup of human malignant gliomas.
Antibodies↗
Local Fas/APO-1 (CD95) ligand-mediated tumor cell killing in vivo.
Fas/APO-1 (CD95) is a cell surface receptor which mediates apoptosis when ligated by specific antibodies or by its recently cloned natural ligand, FasL. We have studied the cytotoxic potential of FasL in vivo using Fas/APO-1-expressing Yac-1 cells as targets. Supernatant harvested from Neuro-2a cells transfected with the murine FasL cDNA contains FasL and transduces a potent apoptotic signal to Yac-1 cells in vitro. Specificity of FasL-mediated cytotoxicity was confirmed by competition assays using soluble Fas or anti-Fas/APO-1 F(ab')2 fragments which specifically interfere with FasL-Fas/APO-1 interactions. Intraperitoneal injection of FasL-containing supernatant efficiently killed Yac-1 target cells which had been implanted in capsules into the peritoneal cavity of mice. Analysis of the target cells revealed DNA fragmentation and nuclear changes typical of apoptosis. As previously shown, intraperitoneal injection of anti-Fas/APO-1 antibodies caused liver failure (Ogasawara, J., Watanabe, F.R., Adachi, M., Matsuzawa, A., Kasugai, T., Kitamura, Y., Itoh, N., Suda, T. and Nagata, S., Nature 1993. 364:806) and was observed at doses which did not reduce Yac-1 cell viability. In contrast, FasL did not induce histopathology in the liver when applied intraperitoneally at doses cytotoxic for Yac-1 cells. However, intravenous administration of FasL induced lethal liver hemorrhages and hepatocyte apoptosis. Thus, locally applied FasL kills tumor cells very efficiently without systemic toxicity and may therefore represent a candidate for local tumor treatment.
Animals↗
T cell apoptosis induced by interleukin-2 deprivation or transforming growth factor-beta 2: modulation by the phosphatase inhibitors okadaic acid and calyculin A.
The phosphatase inhibitors okadaic acid and calyculin A were used to examine the role of phosphorylation processes in T cell apoptosis induced by interleukin-2 (IL-2) deprivation or transforming growth factor-beta 2 (TGF-beta 2). Okadaic acid and calyculin A inhibited IL-2-driven T cell proliferation and induced apoptosis at concentrations known to inhibit protein phosphatase 1. High concentrations of both agents caused toxic changes of prominent cellular swelling and dilatation of rough endoplasmic reticular profiles. When the T cells were induced to undergo apoptosis by IL-2 deprivation, okadaic acid and calyculin A delayed loss of membrane integrity, nucleosomal size DNA fragmentation, and loss of bcl-2 mRNA. However, T cells deprived of IL-2 in the presence of okadaic acid or calyculin A revealed DNA breaks by in situ DNA end labeling and apoptotic morphology by electron microscopy and failed to show enhanced survival after reexposure to IL-2. Although TGF-beta-mediated signaling is thought to involve the dephosphorylation of specific substrates, okadaic acid and calyculin A not only failed to inhibit, but actually augmented, TGF-beta 2-induced inhibition of T cell proliferation and induction of apoptosis. Exposure to either TGF-beta 2 or the phosphatase inhibitors prevented phosphorylation of the retinoblastoma protein RB. In summary, okadaic acid and calyculin A: (i) induce T cell apoptosis in the presence of IL-2, (ii) allow us to distinguish essential from epiphenomenal features of T cell apoptosis after IL-2 deprivation, and (iii) cooperate with TGF-beta 2 in inducing growth arrest and apoptosis of murine T cells via intracellular cascades that converge in the prevention of RB phosphorylation.
Animals↗
The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-beta, T-cell apoptosis, and the immune privilege of the brain.
Human malignant gliomas are rather resistant to all current therapeutic approaches including surgery, radiotherapy and chemotherapy as well as antibody-guided or cellular immunotherapy. The immunotherapy of malignant glioma has attracted interest because of the immunosuppressed state of malignant glioma patients which resides mainly in the T-cell compartment. This T-cell suppression has been attributed to the release by the glioma cells of immunosuppressive factors like transforming growth factor-beta (TGF-beta) and prostaglandins. TGF-beta has multiple effects in the immune system, most of which are inhibitory. TGF-beta appears to control downstream elements of various cellular activation cascades and regulates the expression of genes that are essential for cell cycle progression and mitosis. Since TGF-beta-mediated growth arrest of T-cell lines results in their apoptosis in vitro, glioma-derived TGF-beta may prevent immune-mediated glioma cell elimination by inducing apoptosis of tumor-infiltrating lymphocytes in vivo. T-cell apoptosis in the brain may be augmented by the absence of professional antigen-presenting cells and of appropriate costimulating signals. Numerous in vitro studies predict that tumor-derived TGF-beta will incapacitate in vitro-expanded and locally administered lymphokine-activated killer cells (LAK-cells) or tumor-infiltrating lymphocytes. Thus, TGF-beta may be partly responsible for the failure of current adoptive cellular immunotherapy of malignant glioma. Recent experimental in vivo studies on non-glial tumors have corroborated that neutralization of tumor-derived TGF-beta activity may facilitate immune-mediated tumor rejection. Current efforts to improve the efficacy of immunotherapy for malignant glioma include various strategies to enhance the immunogenicity of glioma cells and the cytotoxic activity of immune effector cells, e.g., by cytokine gene transfer. Future strategies of cellular immunotherapy for malignant glioma will have to focus on rendering glioma cell-targeting immune cells resistent to local inactivation and apoptosis which may be induced by TGF-beta and other immunosuppressive molecules at the site of neoplastic growth. Cytotoxic effectors targeting Fas/APO-1, the receptor protein for perforin-independent cytotoxic T-cell killing, might be promising, since Fas/APO-1 is expressed by glioma cells but not by untransformed brain cells, and since Fas/APO-1-mediated killing in vitro is not inhibited by TGF-beta.
Apoptosis↗
The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis.
In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.
Animals↗
Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation.
The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro. The sensitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibody-mediated killing correlates inversely with the constitutive expression of the antiapoptotic protooncogene bcl-2. Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with malignant transformation in that BCL-2 immunoreactive glioma cells were more abundant in WHO grade III/IV gliomas than in grade I/II gliomas. Fas/APO-1 antibody-sensitive human glioma cell lines stably transfected with a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-mediated apoptosis. Forced expression of bcl-2 also attenuated TNF alpha-mediated cytotoxicity of glioma cell lines in the presence of actinomycin D and cycloheximide and conferred partial protection from irradiation and the cancer chemotherapy drugs, cisplatin and BCNU. Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, which sensitize for Fas/APO-1-dependent killing, partially overcame bcl-2-mediated rescue from apoptosis, suggesting that multimodality immunotherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliomas.
Animals↗
Patient selection and remission rates with the current practice of electroconvulsive therapy in Germany.
The current practice of German psychiatric hospitals restricts electroconvulsive therapy (ECT) to patients with profound disability and failure to respond to pharmacotherapy. We studied clinical features and seizure parameters in 63 patients who received ECT in a 3-year period at a German university hospital. Patients with unipolar and bipolar disorder (depressed) (n = 47) showed a complete or partial recovery as assessed 2 weeks after completion of the ECT course in 31.9 and 38.3%, respectively. Multiple linear regression analysis performed on several clinical and ECT seizure parameters failed to identify strong outcome predictors in our selected sample of patients. Most patients who eventually responded did so early in the course of ECT, while there was little improvement when > 10 ECT treatments were given. Our report highlights the efficacy of ECT in the management of severe psychiatric disorders even in a highly selected sample of patients previously found to be resistant to alternative modes of psychiatric treatment.
Adult↗
Diphenylhydantoin induces apoptotic cell death of cultured rat cerebellar granule neurons.
Apoptosis is one form of physiological or programmed cell death responsible for the selective elimination of various cell types during development. We have observed and characterized a delayed-type of neurotoxicity induced in cultured cerebellar granule neurons by diphenylhydantoin. Diphenylhydantoin toxicity of cerebellar granule neurons is time and concentration dependent. Morphological studies using Nomarski optics and staining with the fluorescent dye Hoechst 33258 demonstrate that diphenylhydantoin-induced neurotoxicity of cerebellar granule neurons is associated with cytoplasmic blebbing, heterochromatic clumping and condensation of chromatin that precede cell death. Unlike glutamate toxicity (excitotoxicity) diphenylhydantoin-induced neurotoxicity of cerebellar granule neurons is attenuated by actinomycin D and cycloheximide, and is associated with nucleosomal size DNA fragmentation. Since we have previously reported that depolarization of cultured cerebellar granule neurons with high concentrations of K+ promotes the survival of these neurons by blocking apoptosis, we examined the effects of diphenylhydantoin on the K(+)-evoked increase in intracellular calcium. Using microfluorimetry and fura-2 to measure intracellular calcium we found that neurotoxic concentrations of diphenylhydantoin markedly reduce the increase in intracellular calcium associated with elevated extracellular potassium. Taken together, these data demonstrate that exposure of cultured cerebellar granule neurons to pharmacologically relevant concentrations of diphenylhydantoin results in a delayed type of neurotoxicity characterized by the biochemical and morphological features of apoptosis.
Animals↗
Depolarization or glutamate receptor activation blocks apoptotic cell death of cultured cerebellar granule neurons.
Cerebellar granule neurons can be readily maintained in culture if depolarized with high concentrations of K+ or subtoxic concentrations of various excitatory amino acids. We now report that these depolarizing stimuli promote cerebellar granule neuron survival by blocking their programmed death via apoptosis. Cerebellar granule neurons maintained in depolarizing conditions and then changed to non-depolarizing conditions, exhibit the morphological and biochemical features of apoptosis, including cytoplasmic blebbing, condensation and aggregation of nuclear chromatin and internucleosomal DNA fragmentation. Inhibitors of RNA or protein synthesis greatly attenuate cell death induced by non-depolarizing culture conditions. In contrast, cerebellar granule neurons, when exposed to fresh serum-containing medium or to high concentrations of glutamate, exhibit a delayed-type of neurotoxicity which is non-apoptotic in nature. Given the actions of excitatory amino acid receptor agonists in preventing apoptosis of cultured cerebellar granule neurons, we hypothesize that the functional innervation of postmigratory granule neurons during cerebellar development may prevent further elimination of these neurons by blocking their programmed death.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Transforming growth factor-beta 2 induces apoptosis of murine T cell clones without down-regulating bcl-2 mRNA expression.
Transforming growth factor-beta (TGF beta) is a potent immunosuppressive cytokine which inhibits the antigen (Ag)-dependent expansion of T cells both in vitro and in vivo by mechanisms not well defined yet. Here we report that exposure of interleukin (IL)-2-dependent T cell lines to TGF beta 2 results in apoptosis defined by morphology, nucleosomal size DNA fragmentation and in situ DNA end labeling. TGF beta 2-induced T cell apoptosis showed the following characteristics: (1) in contrast to the rapid evolution of apoptosis following IL-2 deprivation, apoptosis of T cells triggered by TGF beta 2 was delayed; (2) cycloheximide prevented TGF beta 2-induced apoptosis of CTLL-2 but not of OVA-7 T helper cells; (3) in contrast to apoptosis following IL-2 deprivation, TGF beta 2-mediated T cell apoptosis was not associated with decreased expression of the proto-oncogenes, bcl-2 or c-myc; (4) TGF beta 2-induced apoptosis was not restricted to IL-2-dependent T cell lines since the IL-4-dependent T cell line, CT.4S, as well as EL4 lymphoma cells, which grow independently of exogenous IL-2, were also susceptible to TGF beta 2-mediated apoptosis. Taken together, these data may present a novel mechanism of TGF beta 2-mediated suppression of T cell expansion in response to Ag and IL-2, the activation of the endogenous death program of apoptosis, which appears to operate independently of direct interactions of TGF beta 2 with the IL-2/IL-2 receptor system.
Animals↗
The significance of vitronectin in proliferative diabetic retinopathy.
Vitronectin, an integrin-binding a-1-glycoprotein with potent cell-adhesion and proliferation-mediating properties, has been shown to be incorporated in surgically removed membranes from patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR) and macular pucker. Therefore we developed an ELISA technique to quantify levels of vitronectin in human vitreous and plasma samples in order to be able to evaluate the significance of vitronectin in these different vitreoretinal diseases. Our results indicate a significant increase of vitronectin in all proliferative disorders except idiopathic macular pucker. Adjustment of all probes to equal total protein content yielded a significant increase only in PDR (type II diabetes). Plasma samples demonstrated a significant increase of vitronectin in patients with type II diabetes suffering from PDR. Therefore, break-down of the blood-retina barrier appears to be the most likely explanation for the increased levels of vitronectin in the vitreous. Our results indicate that vitronectin may not only be involved in the regulation of epiretinal membrane formation at significantly higher levels in patients with type II diabetes, but the increase of vitronectin in diabetic plasma may also help to explain the pathological alteration of the coagulation cascade in diabetics.
Blotting, Western↗
NMDA receptor-mediated excitoprotection of cultured cerebellar granule neurons fails to alter glutamate-induced expression of c-fos and c-jun mRNAs.
Exposure of cultured cerebellar granule neurons to subtoxic concentrations of N-methyl-D-aspartate (NMDA) induces a state of excitoprotection when measured by subsequent exposure to toxic concentrations of glutamate. This NMDA-induced excitoprotective state is prevented by inhibitors of new RNA and protein synthesis. Since the neurotrophic and excitoprotective effects of NMDA in cerebellar granule neurons may involve changes in the expression of the immediate early genes c-fos and c-jun, we measured c-fos and c-jun mRNAs in cerebellar granule neurons after exposure to either toxic concentrations of glutamate or excitoprotective (subtoxic) concentrations of NMDA. Exposure of cerebellar granule neurons to toxic concentrations of glutamate induced a dramatic increase in c-fos and c-jun mRNAs which was not associated with a corresponding increase in c-fos and c-jun proteins as measured immunocytochemically. However, the increase in c-fos and c-jun mRNAs induced by toxic concentrations of glutamate was not altered by preexposing cerebellar granule neurons to NMDA, suggesting that increased expression of c-fos and c-jun mRNAs is not sufficient for glutamate toxicity of these neurons. Preexposure of cerebellar granule neurons to NMDA for 24 h, which induced a maximal excitoprotective state, resulted in a transient increase in c-fos, and to a lesser degree c-jun, mRNAs similar to that induced by toxic concentrations of glutamate. The induction of c-fos, but not that of c-jun, mRNA both by excitoprotective concentrations of NMDA and by neurotoxic concentrations of glutamate was blocked by the non-competitive NMDA receptor antagonist, MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗