Search PubMed⌕ Search

Biomedical subjects

M Weller

Publications and source records attributed to M Weller.

At least 235 records · Page 13Linked to original sources
PubMed1994

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) was first recognized as a life-threatening complication of dopamine receptor antagonists characterized by extrapyramidal disturbances, hyperthermia, and elevated serum creatine kinase levels. Concepts of NMS have changed because medications other than classic neuroleptic drugs have been implicated as triggering agents and because syndromes identical to NMS have been observed in patients with Parkinson's disease withdrawn from their medication or suffering akinetic hyperthermic parkinsonian crisis. The neurochemical key features in all these conditions are probably functional dopamine deficiency and ensuing hyperactivity of excitatory amino acid neurotransmission in the basal ganglia and hypothalamus. Recognition of NMS is the most important step in its management; the outcome is good if causative drugs are discontinued or if parkinsonian therapy is readjusted. Supportive care includes management of hyperthermia and fluid replacement. Controversial therapeutic measures include the application of dopamine receptor agonists, excitatory amino acid antagonists, or dantrolene. Psychiatric patients with a history of NMS and psychotic relapse necessitating neuroleptic drugs do not commonly redevelop NMS when reexposed to dopamine receptor antagonists but may be treated most safely with atypical neuroleptic drugs such as clozapine.

Dantrolene↗
PubMed1994

Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines.

Fas/APO-1 is a transmembrane protein of the nerve growth factor/TNF alpha receptor family which signals apoptotic cell death in susceptible target cells. We have investigated the susceptibility of seven human malignant glioma cell lines to Fas/APO-1-dependent apoptosis. Sensitivity to Fas/APO-1 antibody-mediated cell killing correlated with cell surface expression of Fas/APO-1. Expression of Fas/APO-1 as well as Fas/APO-1-dependent cytotoxicity were augmented by preexposure of human malignant glioma cells to IFN gamma and TNF alpha. Further, pretreatment with TGF beta 2, IL1 and IL8 enhanced Fas/APO-1 antibody-induced glioma cell apoptosis whereas other cytokines including TNF beta, IL6, macrophage colony-stimulating factor, IL10 and IL13 had no such effect. None of the human malignant glioma cell lines was susceptible to TNF alpha-induced cytotoxicity. Fas/APO-1 antibody-sensitive glioma cell lines (n = 5), but not Fas/APO-1 antibody-resistant glioma cell lines (n = 2), became sensitive to TNF alpha when co-treated with inhibitors of RNA and protein synthesis. Resistance of human glioma cells to Fas/APO-1 antibody-mediated apoptosis was mainly related to low level expression of Fas/APO-1 and appeared not to be linked to overexpression of the anti-apoptotic protooncogene, bcl-2. Given the resistance of human malignant glioma to surgery, irradiation, chemotherapy and immunotherapy, we propose that Fas/APO-1 may be a promising target for a novel locoregionary approach to human malignant glioma. This strategy gains support from the demonstration of Fas/APO-1 expression in ex vivo human malignant glioma specimens and from the absence of Fas/APO-1 in normal human brain parenchyma.

Antibodies↗
PubMed1994

[Current status of biochemical hypotheses in the pathogenesis of schizophrenia].

The search for neurochemical correlates of schizophrenic psychopathology is a major issue of modern multidimensional approaches to the schizophrenic psychoses. The main focus of interest has shifted in recent years from the classical dopamine hypothesis to an increasing set of various neurotransmitter imbalance models of schizophrenic psychoses involving not only the dopaminergic system but also glutamatergic, serotonergic, cholinergic, GABAergic or peptidergic neuron systems. The pharmacology and phenomenology of phencyclidine-induced model psychoses and a substantial body of neurochemical evidence in human schizophrenic brain suggest that reduced glutamatergic transmission is a key feature in the pathobiochemistry of schizophrenic psychoses and might trigger episodic dopamine excess states, the putative correlates of psychotic relapse. Given the multiple types of natural course, of severity and of prognosis, it is almost inescapable to conclude that there will be no unitary biochemical abnormality underlying the schizophrenic psychoses. None of the available biochemical models of schizophrenia pathogenesis is corroborated by sufficient experimental data. The biochemical data gathered so far have not had a major impact on diagnostic or therapeutic considerations in the schizophrenic psychoses.

Brain↗
PubMed1994

Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties.

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.

Adamantane↗
PubMed1994

The reduced unsubstituted pteroate moiety is required for folate toxicity of cultured cerebellar granule neurons.

The proconvulsive and putative excitotoxic properties of folates led us to study folate toxicity in cultured rat cerebellar granule neurons. Exposure of these neurons to tetrahydrofolate (THF) (EC50 = 263 +/- 12 microM) and dihydrofolate (EC50 = 709 +/- 29 microM), but not to folate, formyl-THF, methyl-THF or methotrexate, resulted in a concentration-dependent neurotoxicity. THF and dihydrofolate toxicity were characterized by prominent neuronal swelling and early loss of neurite networking and could not be blocked by glutamate receptor antagonists, L-channel calcium blockers or anticonvulsants. Cleavage of THF into glutamate and tetrahydropteroate by glutamate carboxypeptidase in the presence of 1 microM MK-801 and 5 microM 6-cyano-7-nitroquinoxaline-2,3,dione shifted the concentration-toxicity curve to the left (EC50 = 47 +/- 4 microM). These results suggest (1) that the glutamate moiety is not necessary for folate toxicity, (2) that the unsubstituted reduced pteroate moiety is required for folate toxicity and (3) that unsubstituted reduced pteroates are previously unrecognized neurotoxins. Because there is no endogenous glutamate carboxypeptidase activity in cerebellar granule neuron cultures and no increase of glutamate levels in the medium of cultures exposed to THF or dihydrofolate, pteroate metabolites are unlikely to mediate the THF or dihydrofolate toxicity of cultured cerebellar granule neurons.

Animals↗
PubMed1993

MK-801 and memantine protect cultured neurons from glutamate toxicity induced by glutamate carboxypeptidase-mediated cleavage of methotrexate.

Cleavage of methotrexate into glutamate and diaminomethylpteroate by intrathecal glutamate carboxypeptidase is a new approach to the treatment of acute methotrexate neurotoxicity. The simulation of glutamate carboxypeptidase rescue from high-dose methotrexate in neuron astrocyte cocultures of rat cerebellum or cerebral cortex resulted in a selective, concentration-dependent neurotoxicity. The neurotoxicity was caused by the enzymatic release of glutamate from methotrexate at lower concentrations of methotrexate, and by both glutamate and diaminomethylpteroate at concentrations of methotrexate exceeding 200 microM. The good neuroprotection afforded by MK-801 and memantine suggested that glutamate toxicity was mediated by N-methyl-D-aspartate receptors. Methotrexate alone was not toxic to astrocytes, neurons, or the neurite networking. [3H]thymidine and [3H]deoxyuridine incorporation studies showed that astrocyte proliferation in the presence of methotrexate was maintained by the reutilization of pyrimidine bases for DNA synthesis. N-methyl-D-asparate receptor antagonists should be coadministered in future experimental and clinical trials examining intrathecal glutamate carboxypeptidase rescue of methotrexate toxicity.

Animals↗
PubMed1993

3-Nitropropionic acid is an indirect excitotoxin to cultured cerebellar granule neurons.

The ability of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to modify 3-nitropropionic acid toxicity was studied in cultured rat cerebellar granule neurons. Exposure of these neurons to 3-nitropropionic acid resulted in a concentration and time-dependent neurotoxicity. In contrast to glutamate toxicity, 3-nitropropionic acid toxicity was potentiated by preexposure to subtoxic concentrations of NMDA. Presumably, the 3-nitropropionic acid-induced energy depletion relieved the voltage-dependent Mg2+ block of the NMDA receptor and induced vulnerability to subtoxic concentrations of NMDA receptor agonists. MK-801 and 2-amino-5-phosphonovaleric acid (APV) delayed but did not prevent 3-nitropropionic acid toxicity, indicating that prolonged exposure to 3-nitropropionic acid ultimately resulted in histotoxic neuronal death. We conclude that there are at least two distinct mechanisms of 3-nitropropionic acid toxicity of cerebellar granule neurons, one indirectly involving NMDA receptor-mediated excitotoxicity and one that is NMDA receptor-independent.

2-Amino-5-phosphonovalerate↗
PubMed1993

N-methyl-D-aspartate receptor agonists decrease protooncogene bcl-2 mRNA expression in cultured rat cerebellar granule neurons.

The protooncogene bcl-2 was studied as a candidate gene for N-methyl-D-aspartate-(NMDA)-induced excitoprotection of cerebellar granule neurons. Exposure of these neurons to excitoprotective concentrations of NMDA and to excitotoxic concentrations of glutamate decreased bcl-2 mRNA levels. Preexposure to NMDA failed to modify the glutamate-evoked decrease in bcl-2 mRNA but increased neuronal survival from 20% to 100%. Neither the intracellular mechanisms underlying the cascade of excitoprotection induced by NMDA nor those underlying the cascade of glutamate toxicity of cerebellar granule neurons seem to specifically involve changes in bcl-2 mRNA levels. Glutamate did not induce nucleosomal DNA fragmentation but glutamate toxicity was inhibited by aurintricarboxylic acid. Glutamate toxicity of cerebellar granule neurons differs considerably from classical programmed cell death.

Actins↗
PubMed1993

NMDA receptor-mediated glutamate toxicity of cultured cerebellar, cortical and mesencephalic neurons: neuroprotective properties of amantadine and memantine.

Effects of amantadine and memantine on NMDA receptor-mediated glutamate toxicity were studied in cultured cerebellar, cortical and mesencephalic neurons. Both drugs protected cerebellar and cortical neurons against glutamate toxicity, memantine being consistently more effective than amantadine but less effective than MK-801. Glutamate toxicity of dopaminergic neurons in mesencephalic cultures was only mildly attenuated by memantine but was also only incompletely blocked by MK-801. These findings suggest that adamantanamines act by inhibiting NMDA receptor-mediated excitatory neurotransmission. However, since non-NMDA receptors appear to be principal mediators of glutamate toxicity of dopaminergic mesencephalic neurons, adamantanamines may fail to protect the nigrostriatal neurons which specifically degenerate in Parkinson's disease.

Amantadine↗
PubMed1993

Anterior opercular cortex lesions cause dissociated lower cranial nerve palsies and anarthria but no aphasia: Foix-Chavany-Marie syndrome and "automatic voluntary dissociation" revisited.

Anarthria and bilateral central facio-linguovelo-pharyngeo-masticatory paralysis with "automatic voluntary dissociation" are the clinical hallmarks of Foix-Chavany-Marie syndrome (FCMS), the corticosubcortial type of suprabulbar palsy. A literature review of 62 FCMS reports allowed the differentiation of five clinical types of FCMS: (a) the classical and most common form associated with cerebrovascular disease, (b) a subacute form caused by central nervous system infections, (c) a developmental form probably most often related to neuronal migration disorders, (d) a reversible form in children with epilepsy, and (e) a rare type associated with neurodegenerative disorders. Bilateral opercular lesions were confirmed in 31 of 41 patients who had CT or MRI performed, and by necropsy in 7 of 10 patients. FCMS could be attributed to unilateral lesions in 2 patients. The typical presentation and differential diagnosis of FCMS provide important clues to lesion localization in clinical neurology. FCMS is a paretic and not an apraxic disorder and is not characterized by language disturbances. Its clinical features prove divergent corticobulbar pathways for voluntary and automatic motor control of craniofacial muscles. Precise clinico-neuroradiological correlations should facilitate the identification of the structural substrate of "automatic voluntary dissociation" in FCMS.

Aphasia↗
PubMed1993

Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects.

Myasthenia gravis (MG) is probably the best studied autoimmune disease caused by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction, subsequently leading to abnormal fatigability and weakness of skeletal muscle. Extraocular muscle weakness with droopy eyelids and double vision is present in about 90% of MG patients, being the initial complaint in about 50%. In approximately 20% of the patients the disease will always be confined to the extraocular muscles. The single most important diagnostic test is the detection of serum antibodies against AChR which is positive in 90% of patients with generalized MG, but only in 65% with purely ocular MG. Electromyographic studies and the Tensilon test are of diagnostic value in clear-cut cases, but may be equivocal in purely ocular myasthenia, especially the latter not rarely producing false-positive results. Treatment response to corticosteroids and anti-cholinesterase agents is satisfactory in many patients with ocular MG, however other immunosuppressive drugs may also be needed. Pathogenetically relevant steps of the underlying autoimmune process have been elucidated during the last few years; nevertheless a number of questions remain open, especially what starts off the autoimmune process, and why are eye muscles so frequently involved in MG?

Autoantibodies↗
PubMed1993

Amantadine and the glutamate hypothesis of schizophrenia. Experiences in the treatment of neuroleptic malignant syndrome.

Amantadine was introduced for the pharmacological management of neuroleptic malignant syndrome (NMS) because of its beneficial effects in Parkinson's disease which were attributed to dopaminomimetic properties. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of the glutamate receptor. Amantadine has psychotomimetic properties in patients with Parkinson's disease and normal controls. Two of four patients who received amantadine for NMS suffered an exacerbation of their psychiatric illness. Our observations support the glutamate hypothesis of schizophrenia which suggests that reduced glutamatergic transmission causes a relative dopaminergic excess in the basal ganglia and the limbic system.

Adult↗
PubMed1993

Intrathecal IgM response in disseminated cerebrospinal metastasis from malignant melanoma.

Neurological complications are a major cause of morbidity and mortality in patients with disseminated malignant melanoma. We have studied and correlated clinical and cerebrospinal fluid (CSF) findings in 20 patients with central nervous system metastases from malignant melanoma including 8 patients with metastatic meningeal melanomatosis (MMM) and 12 patients with solid cerebral metastases (SCM). The putative CSF tumor markers, fibronectin and beta 2-microglobulin, were elevated significantly in MMM but not in SCM patients. A prominent increase in the IgM index, which reflects intrathecal B-cell stimulation, and a rise of IgG index, interleukin-6, and tumor necrosis factor-alpha in MMM patients provide preliminary evidence for a local intrathecal immune response triggered by melanoma cell invasion of the subarachnoid space.

Humans↗
PubMed1993

Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis.

Schizophrenia and Parkinson's disease have been considered inversely related neuropsychiatric disorders since the former has been attributed to increased dopaminergic transmission while the latter is thought to result from loss of dopaminergic neurons. It is in line with this concept that the classical neuroleptic (anti-schizophrenic) drugs cause as a side effect a drug-induced type of Parkinsonism. Most etiopathogenetic models hold that the "neuroleptic malignant syndrome" may result from "over-therapy" of schizophrenia, causing too widespread a block of dopaminergic transmission. The same clinical condition can be triggered by rapid discontinuation of dopaminergic medication in Parkinson's disease. Further, neuroleptic malignant syndrome shares key clinical features such as extrapyramidal motor disturbances and hyperthermia with a severe form of clinical deterioration in Parkinson's disease patients, the akinetic Parkinsonian crisis. Both conditions, neuroleptic malignant syndrome and Parkinsonian crisis, are resistant to anticholinergic treatment but may well respond to drugs with N-methyl-D-aspartate (NMDA) antagonistic properties such as amantadine and memantine. We advocate the use of NMDA receptor antagonists in these medical emergencies and link their clinical efficacy to the common pathophysiological pathway of increased excitatory amino acid neurotransmitter activity in neuroleptic malignant syndrome, Parkinsonian crisis, and dopamine agonist withdrawal states.

Antipsychotic Agents↗
PubMed1993

[Clozapine: a neuroleptic at risk of provoking neuroleptic malignant syndrome (NMS) or an alternative neuroleptic with positive NMS case histories?].

Clozapine is an atypical neuroleptic drug characterised by a striking lack of extrapyramidal side effects. Although these features would seem to make clozapin an unlikely agent for the induction of neuroleptic malignant syndrome (NMS), several putative clozapin-related cases of NMS have recently been reported. A reevaluation of these articles raised some doubts on the causal relationship between clozapin therapy and NMS in most cases. We report on the clinical history of nine consecutive NMS patients who required reinstitution of neuroleptic therapy and received clozapine in our clinic. We conclude (1) that the alleged NMS induction by clozapine monotherapy needs further substantiation and (2) that clozapine should be considered a drug of choice if a psychotic relapse necessitates neuroleptic treatment for patients with a history of NMS.

Adult↗
PubMed1993

A characteristic ganglioside antibody pattern in the CSF of patients with amyotrophic lateral sclerosis.

Paired cerebrospinal fluid and serum samples of patients with amyotrophic lateral sclerosis (n = 35) revealed no consistent abnormalities of CSF cell count, CSF albumin, CSF IgG, CSF IgM, IgG or IgM index, or oligoclonal immunoglobulin band formation in the CSF. Determination of IgG and IgM CSF and serum antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b, and GT1b showed a characteristic pattern which allowed the differentiation of amyotrophic lateral sclerosis from controls and from patients with other neurological disorders including multiple sclerosis. Specifically, patients with the disease had elevated CSF IgM antibodies to all gangliosides except AGM1. The lack of correlation between the CSF findings and corresponding serum antibodies suggests a chronic, compartmental, intrathecal immune response of low activity in amyotrophic lateral sclerosis. Whether this immune response is primary and of pathogenetic significance, or an epiphenomenon of neuronal degeneration, remains to be investigated.

Adult↗