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J Kornhuber

Publications and source records attributed to J Kornhuber.

At least 19 recordsLinked to original sources
PubMed1998

Quantitative analysis of the structural requirements for blockade of the N-methyl-D-aspartate receptor at the phencyclidine binding site.

Blockade of the N-methyl-D-aspartate receptor by uncompetitive antagonists has implications for symptomatic and neuroprotective therapy of various neuropsychiatric diseases. Since the three-dimensional (3D) structure of this ion channel is unknown, the structural requirements for uncompetitive inhibition were investigated by application of a three-step strategy: At first, Ki values were measured for a number of structurally diverse compounds at the phencyclidine (PCP) binding site in postmortem human frontal cortex. Second, a pharmacophore model was developed for this set of molecules employing a mathematical method called graph theory. The resulting pharmacophore provided a very good explanation for the ability of structurally diverse compounds to bind to the same binding site. Using the experimental data and the pharmacophore as a basis for the third step, a three-dimensional quantitative structure-activity relationship (3D-QSAR) applying comparative molecular field analysis (CoMFA) was performed. The QSAR proved to be highly consistent and showed good predictiveness for several additional molecules. The results give a deeper insight into the structural requirements for effective NMDA receptor antagonism and offer the opportunity for improved drug design. The study represents the first quantitative 3D-QSAR model for NMDA receptor blockade, and it comprises structurally very different molecules. That the alignment for a highly consistent CoMFA is based on an automated 3D pharmacophore analysis has important methodological implications.

Binding Sites↗
PubMed1998

The role of glutamate in dementia.

Glutamate is an excitatory neurotransmitter, but may also act as an endogenous neurotoxin. There is good evidence for an involvement of the glutamatergic system in the pathophysiology of dementia. The glutamatergic transmission machinery is quite complex and provides a gallery of possible drug targets. There are good arguments both for an agonist and an antagonist strategy. When following the antagonist strategy, the goal is to provide neuroprotective effects via glutamate receptor antagonisms without inhibiting the physiological transmission that is required for learning and memory formation. When following the agonist strategy, the goal is to activate glutamatergic transmission without neurotoxic side effects. Several available antidementia drugs may modulate the glutamatergic transmission.

Animals↗
PubMed1997

Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is a rare, fatal, neurodegenerative disease caused by a transmissible agent designated as proteinaceous infectious agent (prion). Searching for biochemical markers of CJD, we analysed cerebrospinal fluid (CSF) samples of 53 patients for tau-protein using an enzyme linked immunoassay (ELISA). In a group of 21 patients with definite CJD seen in the German case control study for CJD, tau-protein concentrations in CSF were significantly higher than in two control-groups of patients with other diseases (median 13,153 pg/ml, range 1,533-27,648 pg/ml; P = 0.0001). One group comprised 19 patients who were seen in the same study and were diagnosed as having other dementing diseases (tau concentration: median 558 pg/ml, range 233-1,769 pg/ml). The second control group comprised 13 patients from our hospital with no dementing disease (tau concentration: median 296 pg/ml, range 109-640 pg/ml). We conclude that determination of tau protein levels in CSF is a useful marker for laboratory diagnosis of CJD.

Aged↗
PubMed1997

Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy.

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.

Alzheimer Disease↗
PubMed1997

Oxidative-stress associated parameters (lactoferrin, superoxide dismutases) in serum of patients with Alzheimer's disease.

In this case/control study, serum levels of oxidative stress related parameters such as Fe-binding lactoferrin (LTF), Mn- and Zn,Cu-superoxide dismutase (SOD) were determined by enzyme linked immunoassays in patients suffering from the Alzheimer's dementia as well as in non-demented controls. The Mn-SOD concentration was significantly (P<0.05, U-test) reduced in patients suffering from Alzheimer's disease if compared to non-demented controls. The other parameters investigated did not differ significantly between both groups. Our findings give evidence for the hypothesis of a disturbed free radical metabolism in Alzheimer's disease. The specificity of these results remains to be clarified. Further studies are needed to elucidate the relevance of oxidative stress in the etiopathogenesis of the Alzheimer's disease.

Aged↗
PubMed1997

Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents--preclinical studies.

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.

Amantadine↗
PubMed1997

Dopamine/glutamate interactions in Parkinson's disease.

In Parkinson's disease, the tonic inhibition by basal ganglia output structures may be exacerbated by the action of the subthalamic nucleus. As expected, the reduction of excitatory impact from this structure has been shown to reduce akinesia in monkeys with experimental parkinsonism. The findings of receptor binding studies supporting an increased neuronal activity of efferents of the subthalamic nucleus in patients with Parkinson's disease, suggest that subthalamic nucleotomy or pallidotomy may be effective lesions in the neurosurgical treatment of Parkinson's disease. Systemic administration of glutamate antagonists has been shown to have anti-akinetic effects in animal models of Parkinson's disease. Other observations in monkeys indicate that excitatory amino acids such as glutamate are involved in the pathophysiological cascade of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced neuronal cell death. The neuroprotective effects of competitive and non-competitive NMDA (N-methyl-D-aspartate) receptor antagonists against MPTP toxicity support the hypothesis that NMDA receptor-mediated events are involved in the neurotoxicity of MPTP. Glutamate antagonists may therefore be able to retard the progression and to improve the symptomatology of Parkinson's disease. Several compounds with anti-parkinsonian effects such as amantadine, memantine, budipine and orphenadrine have been shown to be non-competitive NMDA receptor antagonists and are candidates for clinical trials on the neuroprotective efficacy of NMDA receptor antagonism. Furthermore, glutamate antagonists are useful in the treatment of the akinetic parkinsonian crisis, a severe form of clinical deterioration in patients with Parkinson's disease.

Animals↗
PubMed1997

Iodine-123-epidepride-SPECT: studies in Parkinson's disease, multiple system atrophy and Huntington's disease.

UNLABELLED: Epidepride is a benzamide derivative with very high affinity for D2 receptors, which, in its [123I]-labeled form, can be used for SPECT. The aim of this study was to evaluate the usefulness and accuracy of [123I]epidepride-SPECT for the differential diagnosis of movement disorders. METHODS: SPECT imaging with a triple-headed scintillation camera was performed in 9 patients with Parkinson's disease, 9 patients with probable multiple system atrophy (MSA), 1 patient with progressive supranuclear palsy, 16 patients with Huntington's disease (HD) and 14 controls, 3 hr after the intravenous injection of 3.7 +/- 1.3 mCi of [123I]epidepride. The striatum-to-cerebellum ratio - 1, reflecting the specific-to-nondisplaceable binding ratio, was used as a semiquantitative measure of D2 receptor binding. RESULTS: Kinetic studies showed peak striatal uptake about 3 hr postinjection and a slow decline thereafter. The striatum-to-cerebellum ratio - 1 was significantly reduced in MSA (11.8 +/- 3.9, compared to controls, 19.0 +/- 6.3; p < 0.01) and in patients with HD (8.8 +/- 3.2; p < 0.00005) but normal in Parkinson's disease (15.8 +/- 3.6; not significant). A high interindividual variation of specific striatal epidepride binding (striatum - cerebellum; cpm/mCi x kg) was found in controls and in all patient groups. The interindividual variation of striatum-to-cerebellum ratios was lower but still considerable. In half of the MSA patients, the specific-to-nondisplaceable binding ratio fell within the range of controls. The use of various cortical reference regions did not improve discrimination between MSA and controls or Parkinson's disease patients, respectively. The discrimination of HD patients from controls was better, with overlap in only two cases. In one HD patient, calculation of the striatum-to-cerebellum ratio was almost impossible due to extremely low nonspecific binding. Possible explanations for the large variation of the ratios, resulting in an overlap between controls and different patient groups, are very low counting rates in the reference region and the fact that a transient binding equilibrium may not be achieved after bolus injection of epidepride. CONCLUSION: Epidepride appears to be a useful SPECT ligand for studying dopamine D2 receptors. However, its markedly higher specific-to-nondisplaceable binding ratio in comparison to those of iodobenzamide or other D2 ligands did not result in a better discrimination between different basal ganglia disorders. The calculation of plasma input curves and volumes of distribution might improve the accuracy of [123I]epidepride-SPECT.

Adult↗
PubMed1996

A post mortem study on neurochemical markers of dopaminergic, GABA-ergic and glutamatergic neurons in basal ganglia-thalamocortical circuits in Parkinson syndrome.

Functional models of the circuitry of the basal ganglia have recently been proposed to account for the vast spectrum of motor disorders associated with the loss of anatomical or neurochemical integrity within the basal ganglia. On the basis of these hypothetical models, hypokinetic disorders such as Parkinson's disease, are thought to be associated with excessive tonic and phasic inhibition of the output from the basal ganglia to the thalamus. In the present study we have attempted to determine the validity of the proposed model by measuring neurochemical markers of inhibitory and excitatory neurotransmission in post mortem human brain tissue. We have determined the concentrations of the excitatory neurotransmitters aspartate/glutamate and of the inhibitory neurotransmitter GABA in 18 relevant regions of the thalamocortical circuits of the basal ganglia of patients who had manifested Parkinsonian symptoms, and compared them with controls of individuals who had died without any history of neurological or psychiatric disorders and had no neuropathological abnormalities. Additionally, the receptor subtype for the excitatory amino acid N-methyl-D-aspartate (NMDA) was studied in the same brain tissue in which neurotransmitter concentrations had been analysed as neurochemical markers of post-synaptic excitatory neurotransmission. In patients who had manifested Parkinsonian symptoms, glutamate and aspartate levels were found to be unchanged in all examined brain regions. In contrast, the binding of [3H]MK-801, which identifies the NMDA receptor, was reduced in the head (-42%) and body (-38%) of the caudate nucleus. In parkinsonian patients, GABA levels were diminished by 36% in the centromedial thalamus, compared to control values. These results do not confirm the changes in neurotransmitter concentrations predicted according to the model, although we cannot rule out that the predicted changes might have been observed if the Parkinsonian group had been further subdivided into groups diagnosed on the basis of the patients' clinical picture (akinetic-rigid, tremor-dominant, equivalent type) and compared with the control group.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

U-373 MG glioblastoma and IMR-32 neuroblastoma cell lines express the dopamine and vesicular monoamine transporters.

The U-373 MG glioblastoma and the IMR-32 neuroblastoma cell lines were found to express the dopamine (DA) and vesicular monoamine transporters, using reverse transcriptase-polymerase chain reaction (RT-PCR). To further characterize the DA transporter, [3H]GBR-12935 binding and [3H]DA uptake studies were performed. Specific binding of [3H]GBR-12935 to U-373 MG and IMR-32 cells is saturable as saturation experiments indicated. Scatchard analysis revealed two binding sites on U-373 MG as well as on IMR-32 cells. The high-affinity sites exhibited a KD of 2.95 and 0.42 nM and a Bmax of 6.4 and 0.83 fmol/mg protein for U-373 MG and IMR-32 cells, respectively. The low-affinity sites exhibited a KD of 144 and 251 nM and a Bmax of 37.5 and 119 fmol/mg protein for the same cells, respectively. The high-affinity binding of both types of cells probably represents the "classic" DA uptake site identified in other studies from human and rat striatal membranes or synaptosomes, while the low-affinity binding may represent a mazindol-insensitive binding site (the "piperazine acceptor site"). [3H]DA uptake was 0.55 +/- 0.16 and 1.08 +/- 0.33 pmol/mg protein for U-373 MG and IMR-32 cells, respectively. Since the DA transporter has been implicated as an important site for drugs and toxins, the above-mentioned cell lines may be a useful tool in the study of the mechanism of action of DA transporter modulating substances.

Animals↗
PubMed1996

The Gly/Glu polymorphism of the neurotrophin 3 gene: allele frequencies in a Caucasian population and relevance for psychiatric disorders.

Using a modified method for the determination of the genotype of the neurotrophin 3 Gly/Glu polymorphism by PCR, we investigated allele frequencies in patients suffering from different psychiatric diseases as well as in healthy controls. There was a much lower frequency of the allele Glu among Caucasians (0.006) than previously reported for a Japanese population (0.203). No homozygotes and only three heterozygotes for the rare allele could be detected: the latter belonged to the patient group and suffered from endogenous depression (two patients) and hebephrenia (one patient). Due to its very low frequency it seems unlikely that the allele Glu plays a decisive role in the aetiopathogenesis of schizophrenic psychoses or other psychiatric diseases. However, it cannot be excluded that it represents a risk or vulnerability factor.

Adult↗
PubMed1996

A null mutation allele in the CNTF gene and schizophrenic psychoses.

The maldevelopmental theory postulates disturbances in neural development as crucial factors in the aetiopathogenesis of schizophrenia. Neurotrophic factors, including ciliary neurotrophic factor (CNTF), play a central role in the regulation of such development. A mutation has been described for the CNTF gene, whereby subjects homozygous for the mutation lack CNTF. The polymerase chain reaction was used to amplify the CNTF gene region containing this mutation in whole blood genomic DNA. The mutation was detected by analysis of restriction fragment length polymorphisms. Patients suffering from schizophrenic psychosis (ICD-10 criteria) (51 from Würzburg, 83 from Barcelona), and healthy controls (62 from Würzburg, 50 from Barcelona) were investigated. In the Würzburg group, the frequency of subjects homozygous or heterozygous for the mutation was significantly higher among schizophrenic patients than in controls. However, no difference could be detected in the Spanish sample; the possible reasons for the different allele distribution in the two patient groups is discussed. It is concluded that the CNTF null mutation may be relevant to the aetiopathogenesis of schizophrenia in some patients, but further work is required to identify specifically the patient group for which it is important.

Adult↗
PubMed1996

Association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and increased incidence of psychiatric diseases?

We report a possible association between a null mutation in the human ciliary neurotrophic factor (CNTF) gene and psychiatric diseases. Prior findings that the mutant allele frequency is not significantly elevated in patients suffering from neurological diseases are confirmed. The frequency of the mutant allele was higher among psychiatric patients (0.192, n = 297) than among healthy controls and neurological patients (0.142, n = 267). This difference (one-tailed 2 x 2 chi-square test, P < 0.05) might be evidence that disturbances in the neurotrophic factor system could play a crucial role in the etiopathogenesis of psychiatric disorders, mainly psychoses.

Adult↗
PubMed1996

Neurotransmission and the ontogeny of human brain.

The early appearance of neurotransmitters in brain tissue refers to their regulative functions on the neuronal circuits. Many neurotransmitters have direct effects on neuronal outgrowth and differentiation during brain development, which precede their role in synaptic information coding. Both the neurotrophic and neurotoxic properties of excitatory amino acids (EAAs) have focused special interest on glutamatergic neurotransmission during brain development. Therefore, this work intends to review and discuss developmental alterations of the EAA neurotransmitter system in the human brain, their relation to human brain maturation and implications for pathological processes during early human brain development.

Aging↗
PubMed1996

Characterization of [3H]pentazocine binding sites in post-mortem human frontal cortex.

We investigated binding characteristics of [3H](+)-pentazocine in homogenates of post-mortem human frontal cortex. At equilibrium, specific binding was linear with protein concentration, was saturable, reversible, stereoselective, heat-labile and was nearly absent in the white matter. Saturation experiments revealed a KD of 3.68 +/- 0.46nM and a B(max) of 0.636 +/- 0.107 pmol/mg protein. The rank order of Ki values of competing substances was: haloperidol < N,N'-di(o-tolyl)guanidine (DTG) < (+)-SKF 10,047 < (-)-SKF 10,047. We also examined the influence of age, gender, hemisphere, post-mortem time and storage time of brain tissue at -80 degrees C on [3H](+)-pentazocine binding sites. Of these variables, only age was significantly related to [3H](+)-pentazocine binding (diminished binding with increasing age). Together, our results demonstrate the presence of specific [3H](+)-pentazocine binding sites in post-mortem human brain tissue. Furthermore, the binding sites decrease with increasing age and are apparently independent of gender, hemisphere, post-mortem time and storage time of brain tissue.

Adult↗
PubMed1996

[New hypothesis on etiopathogenesis of Alzheimer syndrome. Advanced glycation end products (AGEs)].

Despite intense efforts, it has not yet been possible to clarify the etiopathogenesis of Alzheimer's dementia. There are, however, hypotheses which focus on certain aspects of this type of dementia, characterized by particular neuropathological alterations and clinical correlates. Recently, evidence has accumulated that advanced glycation endproducts (AGEs) could play an important role in the etiology of the Alzheimer's syndrome. AGEs are generated by an irreversible reaction through the non-enzymatic, long-term glycosylation of proteins. They are strongly resistant to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of beta-amyloid into its unsoluble version. AGEs are also demonstrable in neurofibrillary tangles (NFTs). A further mechanism by which AGEs might be pathogenic is via their induction of oxidative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect receptor-mediated mechanisms. Further investigation of AGE-mediated mechanisms should reveal their role in the etiopathogenesis of the Alzheimer's syndrome and, finally, lead to the development of new pharmacological strategies aimed at inhibiting protein cross-linking.

Aged↗