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P Riederer

Publications and source records attributed to P Riederer.

At least 55 records · Page 3Linked to original sources
PubMed2003

Far field potentials from the brain stem after transcutaneous vagus nerve stimulation.

Recently, the vagus nerve has gained particular interest in neuropsychiatry, as neurodegenerative diseases like Alzheimer's and Parkinson's disease are supposed to affect the brainstem nuclei of the vagus nerve early in their course. In addition, electric stimulation of the vagus nerve has therapeutic effects in otherwise therapy-refractory epilepsies and depressions. So far, no method is available to assess vagus nerve function in this context. On this background and based on the established techniques of early acoustic evoked potentials we investigated if a transcutaneous electric stimulation of the sensory auricular branch of the vagus nerve innervating parts of the outer ear is feasible in healthy subjects using this hypothesis-generated approach. We were able to record a clear, reproducible Vagus Sensory Evoked Potential (VSEP) measured as far field potential probably originating in vagus nuclei in the brainstem. Further studies are needed to test the interindividual stability and test-retest reliability of this new method before potential diagnostic and therapeutic applications might be evaluated.

Adult↗
PubMed2003

Arguments for the use of dopamine receptor agonists in clinical and preclinical Parkinson's disease.

On the basis of experimental studies which have demonstrated deleterious effects of L-DOPA (L-3,4-dihydroxyphenylalanine) in vivo and in vitro, it has been suggested that L-DOPA itself may contribute to the progression of Parkinson's disease. This hypothesis is, for many clinicians, the rationale for postponing the employment of and reducing the applied dosage of L-DOPA and for beginning therapy with dopamine receptor agonists or the monoamine oxidase type B (MAO-B) inhibitor selegiline. Furthermore, clinical studies have demonstrated that early treatment with dopamine receptor agonists is associated with a lower incidence of motor fluctuations and dyskinesia. Dopamine receptor agonists exert their symptomatic effect by directly activating dopamine receptors, bypassing the presynaptic synthesis of dopamine and the degenerating nigro-striatal dopaminergic system. They can thus also be of benefit late in the therapy of the disorder. In addition, the pharmacological profile of dopamine receptor agonists suggests a possible neuroprotective effect. This paper reviews briefly the pharmacology of dopamine receptor agonists and basic knowledge concerning the dopamine receptor stimulation which underlies their therapeutic effect. Preclinical approaches for demonstrating neuroprotective effects and their clinical relevance are also discussed.

Animals↗
PubMed2003

The neuromelanin of human substantia nigra: structure, synthesis and molecular behaviour.

The pigmented neurons of the substantia nigra (SN) are typically lost in Parkinson's disease: however the possible relationship between neuronal vulnerability and the presence of neuromelanin (NM) has not been elucidated. Early histological studies revealed the presence of increasing amounts of NM in the SN with aging in higher mammals, showed that NM granules are surrounded by membrane, and comparatively evaluated the pigmentation of SN in different animal species. Histochemical studies showed the association of NM with lipofuscins. However, systematic investigations of NM structure, synthesis and molecular interactions have been undertaken only during the last decade. In these latter studies, NM was identified as a genuine melanin with a strong chelating ability for iron and affinity for compounds such as lipids, pesticides, and MPP+. The affinity of NM for a variety of inorganic and organic toxins is consistent with a postulated protective function for NM. Moreover, the neuronal accumulation of NM during aging, and the link between its synthesis and high cytosolic concentration of catechols suggests a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload.

Aging↗
PubMed2003

[Current preclinical findings on substances against Parkinson's disease].

Striatal dopamine loss provides the premise for dopamine substitution in palliative therapy for Parkinson's disease (PD). This includes firstly L-dopa (L-3,4-dihydroxyphenylalanine, levodopa) and dopamine receptor agonists. Although this therapy has been demonstrated to induce marked clinical improvement in the early stages of PD, its use is limited in the long term by a loss of efficacy. In addition, most patients develop the "long-term L-dopa syndrome," which is characterized by a decrease in the control of Parkinsonian symptoms (decrease in the drug's effect) and the appearance of certain motor disturbances including episodes of akinetic freezing, debilitating dyskinesias, and on-off periods. The aim in developing new drugs is to achieve better therapeutic approaches. In the case of PD, the main strategies are to develop (1) alternatives to L-dopa therapy for alleviating the striatal dopamine deficit while avoiding or retarding the long-term L-dopa syndrome, (2) antidyskinetic approaches, and (3) neuroprotective drugs aimed at causal treatment of PD which is able to preserve the remaining dopaminergic neurones and to halt or at least retard the disease process. This article reviews new approaches for the treatment of PD and presents findings from our studies using a new experimental in vivo model of PD.

Animals↗
PubMed2003

The relevance of preclinical studies for the treatment of Parkinson's disease.

An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).

Antiparkinson Agents↗
PubMed2003

Reduced phosphorylation of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal cortex of patients with major depressive disorder.

In this study, we examined the amounts of cAMP-responsive element binding protein (CREB) and its phosphorylated form in homogenate preparations from postmortem orbitofrontal cortices of antidepressant drug-free patients with major depressive disorder and age-matched controls by immunoblotting. Immunoreactivies of both CREB and phosphorylated CREB were significantly decreased in depressive subjects compared to controls. The immunoreactivity of phosphorylated CREB was diminished to a greater extent than that of CREB in depressive patients. It has been indicated from animal studies that a transcription factor likely mediates neural plasticity in the mammalian brain and neural tissues. Our results suggest that alterations in the cAMP signaling system, especially in CREB, may be involved in the pathophysiology of depression and be potential targets for antidepressant treatment.

Aged↗
PubMed2003

Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum.

The aim of this study was to compare dopamine receptor binding affinities of all currently approved dopamine receptor agonist treatments for Parkinson's disease (PD) in human brain tissue. Alpha-dihydroergocryptine and lisuride displayed higher comparative affinities (Ki=35.4 and 56.7 nM, respectively) for D1 receptors, than the D1/D2 dopamine agonist pergolide (Ki=447 nM). The second generation non-ergot dopamine receptors agonists pramipexole and ropinirole demonstrated no affinity for D1 receptors at concentrations up to 10(-4) M. The ergoline dopamine agonists cabergoline and lisuride displayed the highest affinities for the D2 receptor (Ki=0.61 and 0.95 nM, respectively). Surprisingly, the second generation non-ergot dopamine receptors agonists pramipexole and ropinirole only weakly inhibited binding to D2 receptors (Ki=79.5 and 98.7 microM, respectively using [3H]spiperone). Interestingly we also found that the affinities of cabergoline (Ki=1.27 nM), lisuride (Ki=1.08 nM) and pergolide (Ki=0.86 nM) for the D3 receptor subtype were comparable to that of pramipexole (Ki=0.97 nM). The present results thus support the hypothesis that the antiparkinsonian effect of dopamine receptor agonists is mediated by a more complex interactions with dopamine receptor subtypes than currently believed.

Aged↗
PubMed2003

The dopamine receptor agonist lisuride attenuates iron-mediated dopaminergic neurodegeneration.

Many dopamine agonists used in the treatment of Parkinson's disease are suggested to be potentially neuroprotective. On the basis of its structure, the dopamine agonist lisuride may share this characteristic. In the current study discrete asymptomatic lesions were produced by the injection of iron-laden neuromelanin into the rat substantia nigra and the animals treated with lisuride to determine the protective potential of this substance. Two treatment regimes were utilised. In the neuroprotective protocol, animals were treated with 0.1 mg.kg(-1) lisuride twice daily 3 days prior to, and 7 days following, the iron lesion. In the neurorescue protocol, the animals received 0.1 mg.kg(-1) lisuride twice daily for 1 week beginning on the fourth day post surgery. Eight weeks post surgery, tyrosine hydroxylase-positive neurons surrounding the injection site (33% of total nigral volume) were counted. Dopamine neuron number in iron-lesioned animals was reduced to 50% of that in vehicle-injected animals. The absence of motoric disturbances or a striatal dopamine deficit in these animals suggests a subclinical dopaminergic lesion. Dopamine neuron number in the quantified area in sham-injected animals receiving lisuride or iron-lesioned animals receiving lisuride in both the neuroprotection and neurorescue groups were not significantly reduced. These results suggest that lisuride can protect neurons against iron-induced cell death and might thus be neuroprotective in Parkinson's disease.

Aerobiosis↗
PubMed2003

[Pathomechanisms and hypothesis-guided therapeutic strategies for late-onset Alzheimer's disease].

Even though the clinical effectiveness of the presently used pharmaceutical therapy of sporadic Alzheimer Disease seems to be proven sufficient, their effective mechanisms are much less known or are disregarded in the evaluation of the clinical effects. However, it seems to be inevitable to know both clinical effect and effective mechanisms of pharmaceutics in order to be able to judge their adversity and benefit. In reference to the pharmaceutics implemented on sporadic AD in Germany, total different effective mechanisms are shown. In consideration of the shown pathomechanisms which have been recognized for sporadic AD, therapeutic rationales on application of Ginkgo biloba extract (EGb 761) and Memantine are evident. The application of acetylcholinesterase inhibitors, often looked on as agent of choice, is to be considered critically because of the danger of the occurrence of myopathological dysfunction, resp. the Gulf War Syndrome. Sophisticated and hastily advertised therapy strategies with statins or vaccination against beta A4 should not be used because of a lack of sufficient evidence based on the pathophysiological pattern of damage as known in sporadic AD. Future development must take in account that with sporadic AD aging influences cannot or can hardly be influenced. Therapeutic goals should consist to improve the cellular energy status and the membrane functioning.

Aging↗
PubMed2002

Norepinephrine transporter gene (NET) variants in patients with panic disorder.

Several lines of evidence suggest that catecholamines, especially norepinephrine, are implicated in the etiology and/or symptomatology of panic disorder (PD). At the cellular level, functional noradrenergic neurotransmission depends on synaptic reuptake of norepinephrine as mediated by the norepinephrine transporter (NET). A pharmacological target of agents with an established anti-panic efficacy, e.g. tricyclic antidepressants, the NET is of particular interest in PD. We investigated the NET gene for the presence of 6 naturally occurring exonic sequence variants, 5 of which give rise to amino acid substitutions (Val69Ile, Thr99Ile, Val245Ile, Val449Ile and Gly478Ser) in a population of 87 patients with PD and 89 healthy controls. Except for a silent substitution (G1287A), overall frequencies of variant alleles were low (< or =0.016). None of the variants under study was found to be associated with PD regardless of an additional diagnosis of agoraphobia.

Amino Acid Substitution↗
PubMed2002

Unaltered brain levels of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal in Alzheimer's disease.

In recent years, an important role for the pathogenesis of Alzheimer's disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD.

Age Factors↗
PubMed2002

Free radicals in Parkinson's disease.

Although there are a number of hypotheses to explain the pathobiochemistry of Parkinson's disease (PD), the one on oxidative stress (OS) has gained major interest. The evidence for OS participation as a cause of PD can be summarized as follows: 1) OS is involved in physiological aging, 2) there is ample evidence that OS is significantly enhanced in PD compared to age-matched healthy persons, 3) OS is an early feature of PD because OS-dependent aggregation of proteins in the form of advanced glycation end products can be imaged in Lewy bodies at a time in a person's life, when no phenotype of a neurodegenerative disorder is evident, 4) Experimental models of PD show OS and degeneration of dopaminergic neurons. The toxin-induced neurodegeneration can be blocked by antioxidants, and 5) Activated microglia, known to release free radicals and inflammatory cytokines, are present in brains of Parkinsonian patients. In conclusion, a great body of evidence points to the view that OS is a major component underlying the pathobiochemistry of PD. Together a genetic disposition and endogenous/exogenous toxic events of various origins result in a synergistic cascade of toxicity which leads to dysfunction and finally to cell death of dopaminergic neurons. Again, OS plays a significant role in generating cell death signals including apoptosis.

Animals↗
PubMed2002

Practical importance of neuroprotection in Parkinson's disease.

Consensus could be reached that there is overwhelming evidence of preclinical neuroprotection. However, the evidence of neuroprotection/neurorescue under clinical conditions is limited. Lessons from clinical trials designed to show neuroprotection (selegiline, amantadine, dopamine agonists) demonstrate that with the drugs available neuroprotection/neurorescue has to start as early as possible. A PET-controlled clinical trial with ropinirole shows that there seems to be a good chance for neuroprotection in the early phase of Parkinson's disease in patients treated from the very beginning of the disease while there is no such benefit in patients with a late start of a neuroprotective therapeutic strategy. Also long-term clinical neuroprotection cannot be reached. Complicating factors to demonstrate clinical neuroprotection are discussed.

Amantadine↗
PubMed2002

Involvement of dopamine in the progression of AIDS Dementia Complex.

HIV compromises immunological functions. Immune responses are regulated to a great extent by several molecules such as cytokines, neurotransmitters and hormones which interact with different immune effector cells and ultimately mediate the homeostatic responses to disease. Among these mediators, dopamine plays an important role. In this article we review AIDS Dementia Complex (ADC) and describe lines of evidence implying increased dopamine availability as a potent mediator of neurologic deficits in HIV infection and a factor exhibiting adverse effects on the progression of ADC.

AIDS Dementia Complex↗