Biomedical subjects

Alexander Storch

Publications and source records attributed to Alexander Storch.

At least 19 recordsLinked to original sources

PubMed2007

Valvular heart disease in Parkinson's disease patients treated with dopamine agonists: a reader-blinded monocenter echocardiography study.

Fibrotic valvular heart disease (VHD) has been reported in association with ergot dopamine agonists (DAs), but the current database is insufficient regarding clinical relevance and comparison to data on non-ergot DAs. We evaluated the effects of four DAs (pergolide, cabergoline, ropinirole, pramipexole) on morphology and function of heart valves in patients with Parkinson's disease (PD) to determine the frequency and clinical relevance of DA-induced VHD. A total of 85 patients treated with ergot or non-ergot DAs and 38 age-matched controls were evaluated by transthoracic echocardiography. Valvular pathology was assessed by established criteria of valvular regurgitation and a VHD scoring system. Both grading systems revealed increased frequency of VHD in ergot DA patients compared to both non-ergot DA patients and controls with 22% of ergot DA patients having moderate VHD versus 3% of non-ergot DA patients and none of controls (P = 0.001). We did not find correlations of echocardiographic findings with duration/cumulative dose of treatment, age, or vascular risk factors. Our data suggest that ergot DAs are associated with higher prevalence of VHD compared to non-ergot DAs and controls. Standard echocardiography seems sufficient to detect VHD in PD patients treated with DAs.

Benzothiazoles↗

PubMed2007

Transcription profiling of adult and fetal human neuroprogenitors identifies divergent paths to maintain the neuroprogenitor cell state.

Global gene expression profiling was performed using RNA from adult human hippocampus-derived neuroprogenitor cells (NPCs) and multipotent frontal cortical fetal NPCs compared with adult human mesenchymal stem cells (hMSCs) as a multipotent adult stem cell control, and adult human hippocampal tissue, to define a gene expression pattern that is specific for human NPCs. The results were compared with data from various databases. Hierarchical cluster analysis of all neuroectodermal cell/tissue types revealed a strong relationship of adult hippocampal NPCs with various white matter tissues, whereas fetal NPCs strongly correlate with fetal brain tissue. However, adult and fetal NPCs share the expression of a variety of genes known to be related to signal transduction, cell metabolism and neuroectodermal tissue. In contrast, adult NPCs and hMSCs overlap in the expression of genes mainly involved in extracellular matrix biology. We present for the first time a detailed transcriptome analysis of human adult NPCs suggesting a relationship between hippocampal NPCs and white matter-derived precursor cells. We further provide a framework for standardized comparative gene expression analysis of human brain-derived NPCs with other stem cell populations or differentiated tissues. Disclosure of potential conflicts of interest is found at the end of this article.

Adolescent↗

PubMed2007

Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling.

Oxygen tension is critical for proliferation of human and murine midbrain-derived neural precursor cells (mNPCs). Here, we conditionally inactivated the hypoxia-responsive transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in murine NPCs to determine its role in proliferation, survival, and dopaminergic differentiation in vitro as well as survival of murine dopaminergic neurons in vivo. HIF-1alpha conditional knock-out (HIF-1alpha CKO) mNPCs showed midbrain-specific impairment of survival and proliferation. Dopaminergic differentiation of HIF-1alpha CKO mNPCs in vitro was markedly reduced. Expression of vascular endothelial growth factor (VEGF) mRNA was reduced in HIF-1alpha CKO mNPCs, whereas erythropoietin signaling was not affected. Treatment of HIF-1alpha CKO mNPCs with 50 ng/ml VEGF partially recovered proliferation and dopaminergic differentiation in vitro. In substantia nigra (SN) of adult HIF-1alpha CKO mice, protein levels of dopaminergic marker molecules such as tyrosine hydroxylase (TH) and aldehyde dehydrogenase were reduced by 41 and 61%, respectively. The cell survival marker Bcl-2 was reduced by 58% while caspase-3 was activated. Nonbiased stereological cell counts of TH-positive neurons in SN of young adult HIF-1alpha CKO mice revealed a reduction of 31% compared with cre/wt mice (in which the wild-type Hif1a allele is expressed in parallel with the Cre recombinase allele). However, we found no impairment of striatal dopamine concentrations or locomotor behavior. In conclusion, HIF-1alpha seems to be a transcription factor relevant to the development and survival of substantia nigra dopaminergic neurons involving VEGF signaling.

Animals↗

PubMed2006

Dexamethasone blocks astroglial differentiation from neural precursor cells.

In previous studies, we demonstrated functional neuronal and dopaminergic differentiation of fetal mesencephalic neural precursor cells. The major factors for orienting their progeny towards a dopaminergic phenotype are forskolin and interleukin-1beta. Here, we investigated the effects of dexamethasone (10 microM) on neuronal and glial differentiation. Exposure of mesencephalic neural precursor cells to dexamethasone significantly reduces the amount of glial fibrillary acidic protein astroglia, but not of galactocerebrosidase C oligodendroglia, MAP2ab neurons and tyrosine hydroxylase dopaminergic cells. Presuming a possible involvement of the nuclear factor-kappaB pathway, we examined the effects of wortmannin (phosphatidylinositol 3'-kinase inhibitor) and SN50 (nuclear factor-kappaB inhibitor) on gliogenesis. Both wortmannin and SN50 mimicked the effects of dexamethasone suggesting that dexamethasone specifically blocks astroglial differentiation from mesencephalic neural precursor cells most likely via inhibition of the nuclear factor-kappaB pathway.

Animals↗

PubMed2006

Neurotoxic mechanisms of 2,9-dimethyl-beta-carbolinium ion in primary dopaminergic culture.

beta-Carbolines are potential endogenous and exogenous neurotoxicants that may contribute to the pathogenesis of Parkinson's disease. The 2,9-dimethyl-beta-carbolinium ion (either 2,9-dimethyl-beta-norharmanium or 2,9-Me(2)NH(+)) was found to be neurotoxic in primary mesencephalic cultures and to be a potent inhibitor of mitochondrial complex I. However, the precise mechanisms of cell death remained obscure. Here, we investigated the mechanism of cell death in primary dopaminergic cultures of the mouse mesencephalon mediated by 2,9-Me(2)NH(+). The beta-carboline caused preferential death of dopaminergic neurones, which could not be attributed to cellular uptake via the dopamine transporter. Transient incubation with 2,9-Me(2)NH(+) for 48 h caused a progressive deterioration in the morphology of dopaminergic neurones during a 5-day recovery period and persistent damage to the overall culture. An increase in free radical production and caspase-3 activity, as well as a decrease of respiratory activity, mitochondrial membrane potential and ATP content, contributed to toxicity and pointed to an apoptotic mode of cell death, although a significant quantity of cells dying via necrosis were present simultaneously. These data underline the preferential susceptibility of dopaminergic neurones to 2,9-Me(2)NH(+) as a potent, oxidative stress generating neurotoxin.

Adenosine Triphosphate↗

PubMed2006

Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells.

Neurogenesis in the adult human brain occurs within two principle neurogenic regions, the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Recent reports demonstrated the isolation of human neuroprogenitor cells (NPCs) from these regions, but due to limited tissue availability the knowledge of their phenotype and differentiation behavior is restricted. Here we characterize the phenotype and differentiation capacity of human adult hippocampal NPCs (hNPCs), derived from patients who underwent epilepsy surgery, on various feeder cells including fetal mixed cortical cultures, mouse embryonic fibroblasts (MEFs) and PA6 stromal cells. Isolated hNPCs were cultured in clonal density by transferring the cells to serum-free media supplemented with FGF-2 and EGF in 3% atmospheric oxygen. These hNPCs showed neurosphere formation, expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1 and Olig2, the NSC markers Nestin and Musashi1, the proliferation marker Ki67 and significant activity of telomerase. The phenotype was CD15low/-, CD34-, CD45- and CD133-. After removal of mitogens and plating them on poly D-lysine, they spontaneously differentiated into a neuronal (MAP2ab+), astroglial (GFAP+), and oligodendroglial (GalC+) phenotype. Differentiated hNPCs showed functional properties of neurons, such as sodium channels, action potentials and production of the neurotransmitters glutamate and GABA. Co-culture of hNPCs with fetal cortical cultures, MEFs and PA6 cells increased neurogenesis of hNPCs in vitro, while only MEFs and PA6 cells also led to a morphological and functional neurogenic maturation. Together we provide a first detailed characterization of the phenotype and differentiation potential of human adult hNPCs in vitro. Our findings reinforce the emerging view that the differentiation capacity of adult hNPCs is critically influenced by non-neuronal mesodermal feeder cells.

Adolescent↗

PubMed2006

Transplantation of human neural precursor cells in the 6-OHDA lesioned rats: effect of immunosuppression with cyclosporine A.

Neural precursor cells (NPC) may provide a source for restaurative therapy. We wanted to study the immunogenic potential of human NPC. We transplanted human NPCs with or without cyclosporine A (10 mg/kg) expanded in serum-free conditions into the striatum of rats unilaterally lesioned with 6-hydroxydopamine. Four months after transplantation, there was significant improvement of amphetamine-induced rotational behavior 9 non-immunosuppressed (13.1+/-4.9 pre vs 8.5+/-4.0 after grafting) but nor for 11 animals immunosuppressed with CyA (12.3+/-1.7 vs 11.3+/-2.8). The number of TH-IR cells was comparable in both groups (1,580+/-700 vs 1,274+/-295). All grafted animals only showed mild activation of astrocytes and macrophages within the graft. There was no evidence for tumor formation. Immunosuppression of rats, xenotransplanted with human NPC did not improve graft survival or function.

Amphetamine↗

PubMed2006

Increased periodontal pathology in Parkinson's disease.

Parkinson's disease is characterized by rigidity, akinesia and tremor, all of which interfere with automated small hand movements potentially affecting oral care. In addition, medication and craving for sweets are other risk factors for dental and periodontal disease in these patients. Here, we report the Community Periodontal Index for Treatment Needs (CPITN) data in 70 patients with Parkinson's disease and 85 age-matched control subjects. CPITN indices were assessed in all 6 sextants. Mean CPITN indices of control subjects ranged from 1.6 +/- 0.2 in the upper frontal sextant to 2.5 +/- 0.2 in the upper left lateral sextant. 17.9% of controls showed severely affected teeth (CPITN code 4) in the upper left or upper right sextant, while there were no teeth at risk in the upper frontal sextant. Patients suffering from Parkinson's disease, however, had a markedly increased mean CPITN index in the upper frontal sextant (2.4 +/- 0.2) with 11.5 patients having severely affected teeth (CPITN code 4). CPITN indices in all other sextants were less severely increased. Overall, there was a significant difference between mean CPITN indices of patients and controls (p < 0.05). It seems also noteworthy that female controls had lower CPITN indices in all sextants compared with male controls. This gender difference, however, was reversed in Parkinson's patients. We believe that problems in oral hygiene contribute to this increased periodontal pathology in patients with Parkinson's disease, which may further compromise the quality of life.

Aged↗

PubMed2006

Low extracellular calcium is sufficient for survival and proliferation of murine mesencephalic neural precursor cells.

Various media and Ca2+ concentrations are employed to culture neural progenitor cells (NPCs). We have therefore explored the effects of extracellular calcium concentrations on the survival, proliferation, spontaneous apoptosis and self-renewal capacity of mesencephalic NPCs grown adherently and as free-floating neurospheres. We employed EMEM supplemented with various concentrations of extracellular CaCl2 (0.1-1 mM). Raising the calcium concentration from 0.1 mM to 0.6 mM resulted in an increased number of NPCs growing as a monolayer and increased the protein yield of cells growing in neurospheres (24+/-3 microg total proteins in 0.1 mM Ca2+ medium vs. 316+/-34 microg proteins in 1 mM Ca2+ medium). Concentrations more than 0.6 mM did not result in a further improvement of proliferation or survival. Elimination of calcium from our control medium by 1 mM EGTA resulted in a decrease in cell number from 82+/-2 x 10(4) NPCs/ml observed in control medium to 62+/-2 x 10(4) NPCs/ml observed in calcium-free media. Protein yield dropped significantly in calcium-free media, accompanied by the decreased expression of the proliferation marker PCNA and the pro-survival marker Bcl-2. Two weeks of expansion as neurospheres caused spontaneous cell death in more than 90% of NPCs grown in 0.1 mM CaCl2 EMEM compared with 42% in 1 mM CaCl2 EMEM. Although the action of Ca2+ on NPCs appears to be complex, the presented data strongly suggest that extracellular calcium plays a crucial role in the maintenance of NPCs in a healthy and proliferating state; physiological concentrations (>1.0 mM) are not required, a concentration of 0.5 mM being adequate for cell maintenance.

Animals↗

PubMed2006

Dopamine transporter-mediated cytotoxicity of 6-hydroxydopamine in vitro depends on expression of mutant alpha-synucleins related to Parkinson's disease.

6-Hydroxydopamine (6-OHDA) is widely used to produce animal models of Parkinson's disease (PD) by selectively destroying the nigro-striatal dopaminergic systems, but selective toxicity of 6-OHDA towards dopaminergic cells in vitro remains controversial. Mutant (A30P and A53T) alpha-synuclein isoforms cause increased vulnerability of cells towards various toxic insults and enhance dopamine transporter (DAT)-mediated toxicity of the selective dopaminergic neurotoxin and mitochondrial complex I inhibitor MPP(+) in vitro. Here we extend our recent studies on DAT-mediated toxicity to elucidate the mechanisms involved in selective dopaminergic toxicity of 6-OHDA. We studied the cytotoxicity as well as the toxic mechanisms of 6-OHDA in human embryonic kidney HEK-293 cells ectopically co-expressing mutant alpha-synucleins and the human DAT protein. 6-OHDA showed half-maximal toxic concentration (TC(50)) of 88 microM in HEK-hDAT cells without alpha-synuclein expression after 24 h, whereas the TC(50) values significantly decreased to 58 and 39 microM by expression of A30P and A53T alpha-synuclein, respectively. alpha-Synuclein expression did not affect 6-OHDA toxicity in HEK-293 cells not expressing the DAT. Analysis of intracellular parameters of cellular energy metabolism revealed that the co-expression of mutant alpha-synucleins in HEK-hDAT cells accelerates the reduction of intracellular net ATP levels and ATP/ADP ratios induced by 6-OHDA. Uptake function of the DAT was not altered by expression of alpha-synuclein isoforms. Our data suggest a mechanism of 6-OHDA-induced dopaminergic toxicity involving an interaction of mutant alpha-synucleins with the DAT molecule and subsequent acceleration of cellular energy depletion that might be relevant for the pathogenesis of PD.

Adenosine Triphosphate↗

PubMed2006

Comparative analysis of neuroectodermal differentiation capacity of human bone marrow stromal cells using various conversion protocols.

Human adult bone marrow-derived mesodermal stromal cells (hMSCs) are able to differentiate into multiple mesodermal tissues, including bone and cartilage. There is evidence that these cells are able to break germ layer commitment and differentiate into cells expressing neuroectodermal properties. There is still debate about whether this results from cell fusion, aberrant marker gene expression or real neuroectodermal differentiation. Here we extend our work on neuroectodermal conversion of adult hMSCs in vitro by evaluating various epigenetic conversion protocols using quantitative RT-PCR and immunocytochemistry. Undifferentiated hMSCs expressed high levels of fibronectin as well as several neuroectodermal genes commonly used to characterize neural cell types, such as nestin, beta-tubulin III, and GFAP, suggesting that hMSCs retain the ability to differentiate into neuroectodermal cell types. Protocols using a direct differentiation of hMSCs into a neural phenotype failed to induce significant changes in morphology and/or expression of markers of early and mature glial/neuronal cells types. In contrast, a multistep protocol with conversion of hMSCs into a neural stem cell-like population and subsequent terminal differentiation in mature glia and neurons generated relevant morphological changes as well as significant increase of expression levels of marker genes for early and late neural cell types, such as nestin, neurogenin2, MBP, and MAP2ab, accompanied by a loss of their mesenchymal properties. Our data provide an impetus for differentiating hMSCs in vitro into mature neuroectodermal cells. Neuroectodermally converted hMSCs may therefore ultimately help in treating acute and chronic neurodegenerative diseases. Analysis of marker gene expression for characterization of neural cells derived from MSCs has to take into account that several early and late neuroectodermal genes are already expressed in undifferentiated MSCs.

Adolescent↗

PubMed2006

Early diagnosis of Parkinson's disease.

The clinical methods of olfactory testing and color discrimination as well as apparative methods such as transcranial ultrasound, dopamine transporter imaging and MIBG scintigraphy reveal a high sensitivity concerning the diagnosis of idiopathic Parkinson's disease (PD). The specificity of the presented methods, in particular of the dopamine transporter imaging--seems to be limited. All these methods and primarily their combination allow the detection of PD in early and--probably--preclinical stages. This requires sufficient therapeutic strategies to prevent and treat preclinical and early PD.

Humans↗

PubMed2006

Selective blockage of Kv1.3 and Kv3.1 channels increases neural progenitor cell proliferation.

The modulation of cell proliferation in neural progenitor cells (NPCs) is believed to play a role in neuronal regeneration. Recent studies showed that K(+) channel activity influenced cell proliferation. Therefore, we examined NPCs for K(+) channels and tested whether NPC self renewing can be modulated by synthetic K(+) channel modulators. The whole-cell K(+) current was partly K(+) dependent and showed a cumulative inactivating component. Two tetra-ethyl-ammonium ion (TEA)-sensitive K(+) currents with different voltage dependencies ( = 65 microm, E(50) = -0.3 +/- 1.3 mV and = 8 mm, E(50) = -15.2 +/- 2.8 mV) and an almost TEA-insensitive current were identified. Kaliotoxin blocked approximately 50% of the entire K(+) currents (IC(50) = 0.25 nm). These properties resembled functional characteristics of K(v)1.4, K(v)1.3 and K(v)3.1 channels. Transcripts for these channels, as well as proteins for K(v)1.3 and K(v)3.1, were identified. Immunocytochemical staining revealed K(v)1.3 and K(v)3.1 K(+) channel expression in almost all NPCs. The blockage of K(v)3.1 by low concentrations of TEA, as well as the blockage of K(v)1.3 by Psora-4, increased NPC proliferation. These findings underline the regulatory role of K(+) channels on the cell cycle and imply that K(+) channel modulators might be used therapeutically to activate endogenous NPCs.

Animals↗

PubMed2006

Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signalling.

Isolation and propagation of neural stem cells derived from human brain tissue uniquely enables the study of human neurogenesis in vitro. In addition, ex vivo-expanded human neural stem/precursor cells (NPCs) may offer novel therapeutic strategies. We investigated the effects of extracellular nucleotides on the proliferation and differentiation of human mesencephalic neural stem/precursor cells (hmNPCs). When combined with the mitogens epidermal growth factor and fibroblast growth factor 2, UTP (1 microm) boosted proliferation of hmNPCs as shown by increased expression of the proliferation marker proliferating cell nuclear antigen (330%). UTP-induced proliferation was abrogated by the preferential P2Y receptor blocker pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). UTP also stimulated dopaminergic differentiation. Treatment with UTP (100 microm) increased the number of tyrosine hydroxylase (TH)-positive cells and TH protein by 267 and 319% respectively. UTP-stimulated dopaminergic differentiation of hmNPCs was blocked by the P2 receptor antagonists suramin (10 microm) and PPADS (100 microm). In addition, UDP (1 microm) enhanced TH protein expression by 194%. During differentiation, treatment with UTP stimulated the extracellular signal-regulated kinase (ERK) pathway. Both ERK1/2 phosphorylation and dopaminergic differentiation were inhibited by U0126, a selective ERK kinase inhibitor, as well as by suramin. When other P2 receptor agonists (ATP, ADP and adenosine 5'-O-(2-thiophosphate) (ADPbetaS); all 100 microm) were applied, both proliferation and dopaminergic differentiation of NPCs were compromised. We conclude that uracil nucleotides exert specific P2 receptor-mediated effects on midbrain-derived human NPCs, and may be used to enhance both proliferation and dopaminergic differentiation.

Adenine Nucleotides↗

PubMed2006

Developmental perspectives on human midbrain-derived neural stem cells.

Regeneration or restoration of lost or damaged neurons is very likely to profoundly alter the disability and needs of many patients. The replacement of dopaminergic (DA) neurons in patients with Parkinson's disease via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications. Ethical concerns related to the use of fetal tissue derived from abortions further argue for the search for alternative tissue sources. Today, it seems possible to generate functional DA neurons from a variety of stem cells, including embryonic and neural stem cells. Bone marrow stromal cells are another source for cell replacement. Neural stem cells derived from human fetal midbrain tissue maintain a considerable capacity to self-renew and to differentiate into DA neurons. Therefore, these cells may be a promising source to generate functional human DA neurons.

Humans↗

PubMed2006

Epigenetic conversion of human adult bone mesodermal stromal cells into neuroectodermal cell types for replacement therapy of neurodegenerative disorders.

Tissue-specific stem cells, such as bone marrow-derived mesodermal stromal cells (MSCs), are thought to be lineage restricted and, therefore, could only be differentiated into cell types of the tissue of origin. Several recent studies, however, suggest that these types of stem cells might be able to break barriers of germ layer commitment and differentiate in vitro and/or in vivo into cells of different tissues, such as neuroectodermal cell types. Recently, protocols for high-yield generation of undifferentiated neural stem cell (NSC)-like cells from MSCs of primate and human origin were reported. Undifferentiated NSCs are commonly used and are more suitable for neurotransplantation compared with fully differentiated neural cells, as differentiated neural cells are well known to poorly survive detachment and subsequent transplantation procedures. These human MSC-derived NSC-like cells (MSC-NSCs) grow in neurosphere-like structures and express high levels of early neuroectodermal markers, but lose characteristics of MSCs. In the presence of selected growth factors, human MSC-NSCs can be differentiated into the three main neural phenotypes: astroglia, oligodendroglia and neurons. Compared with direct differentiation of human MSCs into mature neural cells, the conversion step seems to be essential to generate mature functional neuroectodermal cells. This review describes the techniques for the conversion of human MSCs into NSCs and summarises the data on epigenetic conversion of human MSCs into immature neuroectodermal cells. These cells provide a powerful tool for investigating the molecular mechanisms of neural differentiation, and might serve as an autologous cell source to treat acute and chronic neurodegenerative diseases.

Adult↗

PubMed2005

Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.

Neurogenesis in the adult brain occurs within the two principal neurogenic regions: the hippocampus and the subventricular zone of the lateral ventricles. The occurrence of adult neurogenesis in non-neurogenic regions, including the midbrain, remains controversial, but isolation of neural stem cells (NSCs) from several parts of the adult brain, including the substantia nigra, has been reported. Nevertheless, it is unclear whether adult NSCs do have the capacity to produce functional dopaminergic neurons, the cell type lost in Parkinson's disease. Here, we describe the isolation, expansion, and in vitro characterization of adult mouse tegmental NSCs (tNSCs) and their differentiation into functional nerve cells, including dopaminergic neurons. These tNSCs showed neurosphere formation and expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, and Olig2, the NSC markers Nestin and Musashi1, and the proliferation markers Ki67 and BrdU (5-bromo-2-deoxyuridine). The cells showed typical propidium iodide-fluorescence-activated cell sorting analysis of slowly dividing cells. In the presence of selected growth factors, tNSCs differentiated into astroglia, oligodendroglia, and neurons expressing markers for cholinergic, GABAergic, and glutamatergic cells. Electrophysiological analyses revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels, action potentials, as well as currents induced by GABA (gamma-aminobutyric acid), glutamate, and NMDA (N-methyl-D-aspartate). Clonal analysis demonstrated that individual NSCs retain the capacity to generate both glia and neurons. After a multistep differentiation protocol using co-culture conditions with PA6 stromal cells, a small number of cells acquired morphological and functional properties of dopaminergic neurons in culture. Here, we demonstrate the existence of adult tNSCs with functional neurogenic and dopaminergic potential, a prerequisite for future endogenous cell replacement strategies in Parkinson's disease.

Animals↗

PubMed2005

High doses of pergolide improve clinical global impression in advanced Parkinson's disease:- a preliminary open label study.

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate to severe Parkinson's disease (PD) in an open-label multicenter clinical trial. The primary objective was to assess the amount of reduction in levodopa, the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of 12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a maximum of 12 mg/day in combination with a simultaneous decrease of levodopa doses in 100mg steps. Levodopa was reduced from 500 mg/day (median) to 250 mg/day. Mean UPDRS part III improved significantly (p=0.01). Clinical global impression improved significantly after 24 weeks (p<0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal pain, and peripheral edema. Twenty-two patients finished the complete study according to protocol. A possible relationship to the study medication was assumed for two serious adverse events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced stages of PD if given in appropriate regimens.

Adult↗