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P Riederer

Publications and source records attributed to P Riederer.

At least 325 records · Page 18Linked to original sources
PubMed1993

Isolation of a cDNA encoding the human brain serotonin transporter.

A cDNA encoding a serotonin transporter (5-HTT) in the human dorsal raphe nucleus was isolated and sequenced using cross-species amplification of human 5-HTT partial cDNA by the polymerase chain reaction (PCR) and the RACE-PCR procedure, designed for rapid amplification of 3' and 5' cDNA ends. The cDNA contains an open reading frame encoding a hydrophobic polypeptide of 630 amino acids with a calculated molecular weight of approximately 70 kDa. The human 5-HTT is approximately 92% homologous to the rat protein but contains an additional consensus phosphorylation site for cAMP-dependent protein kinase recognition located in the cytoplasmic N-terminal region, while a potential protein kinase C phosphorylation site identified in the rat homolog is not conserved in the human 5-HTT. Hydropathicity analysis revealed twelve membrane spanning segments, a topology proposed for other cloned sodium-dependent transporters.

Amino Acid Sequence↗
PubMed1993

Extensive sequence divergence between the human and rat brain vesicular monoamine transporter: possible molecular basis for species differences in the susceptibility to MPP+.

A cDNA encoding the human brain vesicular monoamine transporter (VMT) was isolated and sequenced using PCR. The cDNA contains an open reading frame encoding a hydrophobic polypeptide of 514 amino acids with twelve membrane spanning segments, a calculated molecular weight of 55,709 Da, and an estimated isoelectrical point of 5.62. A structurally identical transporter is expressed in human platelets. Two intraplasmatic consensus phosphorylation sites of cAMP-dependent protein kinase recognition and two potential protein kinase C phosphorylation sites may be central to the regulation of the VMT. Although the human brain VMT is 90.7% homologous to the rat protein, an extensive sequence divergence occurs in the large luminal loop located between the first two transmembrane domains. This loop displays a remarkably reduced homology of 64.0% with several deletions and insertions, although four putative glycosylation sites are conserved. Since functional vesicular monoamine transport suppresses MPP+ toxicity and sequence divergence in the large luminal loop of the VMT expressed in rat brain and adrenal medulla may play a role in differential neurotoxic effects of MPP+, our findings indicate one possible molecular basis for the substantial species differences in the susceptibility to MPP+ demonstrated among humans, non-human primates, and rodents. They are also likely to facilitate molecular pharmacologic and genetic investigations of the human VMT in neurodegenerative disorders.

Amino Acid Sequence↗
PubMed1993

Imbalance of the Gs and Gi/o function in post-mortem human brain of depressed patients.

The amounts of various G protein subunits in postmortem brain samples from the parietal and temporal cortices were the same in controls and depressive patients as demonstrated by immunoblotting. However, photoaffinity GTP labeling (AAGTP) of Gi/o alpha, but not Gs alpha, was significantly increased in depressives in both cortex regions. Furthermore, the ratio of Gs/Gi/o AAGTP incorporation revealed a significant reduction in depressives in these regions. The present findings suggest that an imbalance of second messengers via G protein function may be involved in the pathophysiology of depression.

Affinity Labels↗
PubMed1993

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition.

The "cheese effect", potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible non-selective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with non-selective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.

Animals↗
PubMed1993

L-glutamate and L-aspartate concentrations in the developing and aging human putamen tissue.

We have previously reported that the developmental regulation of NMDA receptor expression in human brain is characterized by a sharp postnatal increase peaking at about age 1 year. We have now extended this work by measuring concentrations of L-glutamate and L-aspartate in the putamen from 45 human autopsy specimens. Both amino acids increased steeply within the first postnatal year after which they remained fairly constant throughout life. There was no impact on glutamate and aspartate levels in putamen of sex, side of the brain, postmortem time and storage time of brain tissue.

Adolescent↗
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

The thiobarbituric acid assay reflects susceptibility to oxygen induced lipid peroxidation in vitro rather than levels of lipid hydroperoxides in vivo: a methodological approach.

Although the hypothesis of oxidative stress as a pathogenetic factor of neurodegenerative diseases became a matter of interest recently, direct evidence supporting this hypothesis is rare. The most prominent assay being currently used as an index for lipid peroxidation products in vivo is the thiobarbituric acid assay. Thiobarbituric acid reactive substances are mainly formed during the decomposition of lipid hydroperoxides in vitro. It is questionable however, that all species detectable with thiobarbituric acid are derived from in vivo preformed lipid hydroperoxides. These studies were undertaken to investigate the influence of autoxidation reactions on colour production during the acid heating stage of the assay. If driven aerobically, more than 90% of thiobarbituric acid reactive substances are newly generated in vitro during incubation at 95 degrees C for 75 min. This process can be enhanced by addition of ferric iron. Chain breaking antioxidants like butylated hydroxytoluene decrease colour formation in the absence or in the presence of iron. If driven anaerobically under argon, colour formation was only 10% of aerobically heated homogenates or lipid extracts of human brain tissue. These results may indicate that measurement of thiobarbituric acid reactive substances under the aerobic conditions described here reflects to a great extent the susceptibility of brain tissue or lipids to oxygen-induced formation of lipid hydroperoxides in vitro rather than degradation products of in vivo performed lipid hydroperoxides.

Aged↗
PubMed1993

Effects of nimodipine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced depletions in the biogenic amine levels in mice.

In view of the calcium hypothesis the effect of nimodipine (Bay e 9736, CAS 66085-59-4) on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletions in dopamine and serotonin were investigated in C57-BL/6 mice. Oral treatment with nimodipine (5 mg/kg and 20 mg/kg b.i.d., respectively, for 9 days) prior to, during and following administration of MPTP appeared to attenuate MPTP-induced neurochemical changes in a dose-related manner. The results suggest that nimodipine reduces MPTP-induced damages, especially in the serotoninergic system, through its calcium antagonistic effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Recent advances in pharmacological therapy of Parkinson's disease.

The discovery of a selective striatal dopamine deficiency in Parkinson's disease has led to dopamine replacement therapies including L-DOPA, dopamine full and partial agonists, and MAO-B inhibitors. The development of new compounds and alternative methods of drug delivery may be able to overcome the long-term side effects of the established therapies. Overactivity of central glutamatergic systems appears to be important in the pathophysiology of the disorder and provides the rationale for the use of glutamate antagonists. Recent studies emphasize the significance of oxidative stress and free radical formation in the pathogenesis of Parkinson's disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of the disease. Possible neuroprotective strategies include selective MAO-B inhibitors, iron chelators, and free radical scavengers.

Antiparkinson Agents↗
PubMed1993

Involvement of transmitter systems in neuropsychiatric diseases.

Normal function of the central nervous system (CNS) requires intact morphology as well as neurotransmission. Diseases of the CNS can become manifest as a sensorimotor deficit or psychic alteration, or both. When observing neuropsychiatric diseases, interaction of different transmitter systems is obvious. Thus, an increase or a decrease of transmitter systems affect each other. Mechanisms of compensation can also lead to alterations in transmitter systems not involved in the pathological process. Parkinson's disease, hyperkinetic movement disorders like ballism and Huntington's chorea, epilepsy and anxiety will be used in this paper as examples of the synergistic action of dopaminergic, peptidergic, glutamatergic, GABAergic and cholinergic neurotransmission. With our knowledge of the functional balance of transmitter systems in the CNS, various pharmacological strategies have been available to intervene in the pathophysiological process. The excitatory or inhibitory quality of the transmitter systems must be considered if such strategies are to be employed. On the other hand, a functional balance between two or more transmitter systems may cause a contrary therapeutic intervention on the opposite side of the balance.

Anxiety Disorders↗
PubMed1993

The role of iron in senescence of dopaminergic neurons in Parkinson's disease.

In Parkinson's disease (PD) an elevation of iron with staging of the disease has been observed in the substantia nigra (SN), especially the zona compacta (ZC). The iron is found to be present in glia, active microglia, macrophages, oligodendrocytes, outside the degenerated dopamine neurons and as a mild halo around Lewy bodies and within melanized dopamine neurons of SNZC. Although in control brains iron is absent in melanized dopamine neurons, in PD it is bound to neuromelanin in a fashion similar to the interaction of iron with synthetic dopamine-melanin. The iron in SNZC is thought to induce oxidative stress and thus be associated with the reported decreases of glutathione peroxidase activity, reduced glutathione (GSH), mitochondrial Complex I activity, calcium binding protein and increase of basal lipid peroxidation. An animal (rat) model of PD has been described in which intranigral iron injection induces a relatively specific lesioning of dopamine neurons resulting in behavioural and biochemical Parkinsonism in rats. Support for the neurotoxicity of iron liberated from an endogenous source has come from the 6-hydroxydopamine model of PD. This neurotoxin is thought to owe its toxicity to the liberation of iron from ferritin, which in turn alters the homeostasis of mitochondrial Ca2+ with the subsequent depletion of tissue GSH, resulting in oxidative stress. Pretreatment of rats with intraventricular injection of a relatively selective prototype iron chelator, desferrioxamine (desferal), attenuates the 6-hydroxydopamine lesion of nigrostriatal dopamine. Thus iron can fulfill the role of a neurotoxin. However it remains to be established whether its role in PD is primary or secondary to some other neurotoxic event.

Aging↗
PubMed1993

[Effects of ethanol on GTP-binding protein function in human brain cortex].

The effect of ethanol "in vitro" on GTP-binding protein in postmortem human brain cortex membranes was analyzed using by photoaffinity hydrolysis resistant GTP analog (azidoanilido GTP, AAGTP). AAGTP identified stimulatory GTP binding protein [Gs alpha (42 KDa)] and inhibitory GTP binding protein [Gi alpha (40 KDa)] in human brain cortex membranes. Ethanol augmented the amount of AAGTP binding to both Gs alpha and Gi alpha in human temporal and parietal cortex membranes. These results show that ethanol "in vitro" elevates not only Gs functions but also Gi functions in postmortem human brain cortex.

Aged↗