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  • 1
    ISSN: 1432-1106
    Keywords: Differential-pulse voltammetry ; Dopamine ; Caudate putamen ; Neural grafting ; Non-grafted side ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study employed differential-pulse voltammetry to assess the influence of foetal ventral mesencephalic grafts on dopamine overflow in the contralateral caudate putamen of the 6-hydroxydopamine rat model of Parkinson's disease. The experimental design involved measurements of dopamine overflow in the grafted and contralateral striatum. Control measurements of dopamine overflow were performed in 6-hydroxydopamine-lesioned rats only and the caudate putamen of normal control rats. Cell suspensions of foetal rat ventral mesencephalic tissue were grafted into the dopamine-depleted caudate putamen of unilaterally 6-hydroxydopamine-lesioned rats. At 6 weeks, animals with functional, mature grafts (as assessed by amphetamine-amplified behavioural asymmetry), were pretreated with pargyline (75 mg/kg i.p.), and both striatal sides were monitored for dopamine overflow for 90 min following amphetamine sulphate administration (5 mg/kg i.p.). The time course of dopamine overflow inside the graft was similar to that in the contralateral caudate putamen of the same animal, the normal control animal and the contralateral caudate putamen of 6-hydroxydopamine-lesioned animals. However, in grafted animals the mean dopamine overflow detected in the contralateral caudate putamen was approximately 34% lower than the concentration of dopamine detected in the contralateral caudate putamen of 6-hydroxydopamine-lesioned control animals and approximately 39% lower than the concentration of dopamine detected in the caudate putamen of the normal control animal. There was no statistical difference in the concentration of amphetamine-induced dopamine overflow between the caudate putamen contralateral to the 6-hydroxydopamine lesion and the caudate putamen of the normal control animal. These data suggest that intrastriatal foetal ventral mesencephalic suspension grafts reduce amphetamine-induced dopamine release in the contralateral non-grafted caudate putamen.
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  • 2
    ISSN: 1432-1106
    Keywords: Key words Brain transplantation ; MIF ; MSF ; 6-OHDA ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Activated microglia play an important role in the rejection of intracerebral grafts and the degeneration of axotomized neurones. We studied the effect of macrophage migration stimulatory factor (MSF) or macrophage migration inhibitory factor (MIF) on allogeneic foetal mesencephalic dopaminergic grafts transplanted into the striatum of 6-hydroxydopamine-lesioned rats. Rotation testing revealed a significant compensation of lesion-induced motor asymmetry 3 weeks post-grafting in animals treated with MIF and vehicle-treated controls compared with pre-graft values (Student′s t-test, P≤0.005) and MSF-treated animals (ANOVA, post hoc Fisher PLSD test, P≤0.05). The MSF group showed no significant compensation. Graft recipients with MIF application (1452.06 ± 164.32 tyrosine hydroxylase-positive ventral mesencephalic cells) and controls (1753.21 ± 165.51 tyrosine hydroxylase-positive neurones) displayed good graft survival. Animals with MSF application showed a significant reduction of tyrosine hydroxylase-positive grafted cells (MSF 570.36 ± 209.49 cells) and graft volumes compared with the MIF and the control group (ANOVA, post hoc Fisher PLSD test, P≤0.05). The propotional area of microglia was significantly reduced in MIF animals compared with control animals (ANOVA, post hoc Fisher PLSD test, P≤0.001). Activated microglia and macrophages were reduced by half in the MIF-treated group compared with MSF animals and controls. We conclude that intrastriatal injections of MSF result in impaired function and survival of allogeneic ventral mesencephalon (VM) grafts 3 weeks after transplantation. MIF can reduce the number of microglia and macrophages in allogeneic foetal VM grafts. A reduction of microglia via MIF application did not enhance graft function and survival.
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  • 3
    ISSN: 1432-1106
    Keywords: Basal ganglia ; Transmitters ; Neuropeptides ; GABA ; Enkephalin ; Striato-nigral pathways
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of striatal ibotenic acid lesions on dynorphin-, substance P- and enkephalin-like immunoreactivities in the substantia nigra has been studied with immunohistochemistry as well as biochemistry. A comparison was made with the effects produced by intranigral ibotenic acid lesion and by 6-hydroxy-dopamine injection into the medial forebrain bundle. In addition, the effect of the striatal lesions on nigral glutamic acid decarboxylase (GAD)-positive structures was analysed with immunohistochemistry. The effect of the lesions was analysed functionally in the Ungerstedt rotational model, in order to obtain a preliminary evaluation of the extent of the lesions. The striatal lesions produced a parallel depletion of dynorphin and substance P levels in the substantia nigra, pars reticulata, ipsilateral to the treated side, which was dependent upon the extent and location of the lesion. Ibotenic acid lesions into the tail and the corpus of the striatum produced stronger nigral-peptide depletion than lesions in the head and the corpus of the striatum. Comparison of placement of lesions and localization of depleted area in the substantia nigra revealed a topographical relationship. Furthermore, the nigral depletion patterns of dynorphin and substance P were similar. The immunohistochemical analysis revealed that also GAD-positive fibers in the pars reticulata to a large extent disappeared after striatal lesions, in parallel to the dynorphin- and substance P-positive fibers. However, the depletion was less pronounced for GAD than for the peptides, probably related to presence of local GABA neurons in the zona reticulata of the substantia nigra. These results indicate that with the types of lesion used in this study it is not possible to provide evidence for a differential localization within the striatum of dynorphin-, substance P- and GABA-positive cell bodies projecting to the substantia nigra. The radioimmunoassay showed that (Leu)- but not (Met)-enkephalin was affected to the same extent as the dynorphin peptides, supporting the view that (Leu)-enkephalin in the pars reticulata of the substantia nigra is derived from proenkephalin B and not from proenkephalin A. In the immunohistochemical analysis (Met)-enkephalin-like immunoreactivity could only be detected in the pars compacta of the substantia nigra and did not seem to be affected by any of the lesions. The striatal lesions produced a behavioural asymmetry, which could be disclosed by stimulating the rats with apomorphine, which produced ipsilateral rotation. The total number and intensity of the rotation were closely correlated to the extent and location of the striatal lesion as well as to the amount of dynorphin and substance P depletion found in the substantia nigra of the treated side. The results provide further evidence for the presence of a dynorphin-containing system with fibers originating mainly in the corpus and tail of the striatum and terminating in the zona reticulata of the substantia nigra and may, similarly to the previously characterized substance P and GABA containing pathways, have a role in the control of motor behaviour.
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  • 4
    ISSN: 1432-1106
    Keywords: Key words Parkinson’s disease ; Dopamine ; Substantia nigra ; Striatum ; 6-Hydroxydopamine lesion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Intrastriatal application of 6-hydroxydopamine (6-OHDA) initiates a delayed and progressive loss of nigral dopaminergic neurons and therefore may better resemble the slowly developing neuropathology of Parkinson’s disease. We investigated the anatomical, behavioural and biochemical consequences of intrastriatal 6-OHDA after prior labelling of nigral dopaminergic neurons in rats and whether the dihydropyridine L-type calcium channel blocker nimodipine protected from the induced deficits. Adult rats received bilateral intrastriatal injections of the retrograde fluorescence tracer fluorogold and nimodipine (n=12) or placebo (n=9) pellets implanted subcutaneously. One week later all rats were injected unilaterally with 6-OHDA (20 μg) at the same intrastriatal site. Placebo-treated rats displayed relatively few d-amphetamine-induced ipsilateral net rotations (R) (1.3±1.4 R/min; mean±SEM) 1 week after the lesion with a slight but non-significant decline thereafter (after 2, 3 and 4 weeks). In nimodipine-treated rats the rotation behaviour after 1 week was more prominent (3.5±0.8 R/min; mean±SEM) with a similar slight decline until week 4. Fluorescent and immunocytochemical analysis of the midbrain after 4 weeks revealed a 35% and 39% loss of tyrosine hydroxylase positive cells and a 62% and 56% (placebo and nimodipine, respectively) loss of fluorogold-labelled cells in the ipsilateral substantia nigra pars compacta. Striatal dopamine levels were reduced to 47% (placebo) and 43% (nimodipine) of the control side and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to about 50%. Pretreatment with nimodipine failed to antagonize or to ameliorate any of the lesion-induced deficits. We conclude that pretreatment with 80 mg nimodipine pellets does not prevent nigrostriatal damage induced by intrastriatal 6-OHDA.
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cysteine sulfinate decarboxylase (CSD), the putative biosynthetic enzyme for taurine, has been shown to exist in two forms in rat brain, respectively CSDI and CSDII, one of which (CSDII) is considered to be in fact glutamate decarboxylase (GAD). CSDI assay after immunotrapping was made possible by using an anti-CSD antiserum raised in sheep immunized with a partially purified CSD fraction from liver. This antiserum immunoprecipitated both liver CSD and brain CSDI activities with the same affinity but did not inhibit their enzymatic activities. The immunotrapping of CSDI was selective without any contamination by GAD/CSDII activity. The immunotrapped CSD activity, which corresponded exactly to the amount of CSD not precipitated by a GAD/CSDII antiserum, was not inhibited by a specific irreversible GAD inhibitor. A quantitative, selective and sensitive assay was thus developed by measuring CSD activity on the solid phase after immunotrapping. Kinetic parameters of the immunotrapped enzyme remained unchanged. CSDI activity represented only a fraction, around 20% with saturating concentration of substrate, of the total CSD activity in rat brain homogenate. This indicates that most studies on total CSD activity dealt essentially with CSDII activity that is indeed GAD. Regional and subcellular distributions of CSDI have been determined. CSDI activity was about threefold higher in the richest (cerebellum) compared to the poorest (striatum) region without any correlation with GAD/CSDII distribution. Subcellular distribution showed a fourfold enrichment of CSDI activity in the synaptosomal fraction. The precise role of CSDI and CSDII in the biosynthesis of taurine in vivo remains to be elucidated.
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  • 6
    ISSN: 1435-1463
    Keywords: Parkinson's disease ; folinic acid ; tetrahydrobiopterin- and tetrahydrofolate metabolism ; motor performance series
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Folinic acid (15 mg bid, po) was administered in a two week, double-blind, placebocontrolled, cross over clinical trial in 5 patients with Parkinson's disease (Hoehn and Yahr stage I or II). 4 patients had not been on L-dopa treatment prior to entering this trial and one patient was on a small dose of L-dopa. No significant improvement could be detected in this pilot study by clinical evaluation and motor performance assessed by a computer assisted motor performance test.
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  • 7
    ISSN: 1435-1463
    Keywords: Spiperone binding ; Parkinson's disease ; multiple system atrophy ; vascular lesions ; differential diagnosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In order to investigate the diagnostic value of3H-spiperone binding capacity to lymphocytes in the differential diagnosis of de novo Parkinson's disease (idiopathic Parkinson syndrome, PD), we performed a double blind prospective study of spiperone binding capacity of 123 patients and 23 healthy control persons, belonging to different diagnostic groups (PD, Parkinsonian syndrome due to vascular lesions, multiple system atrophy [MSA], essential tremor). Diagnoses were based on medical history, clinical examination, CT or MRI scan, acute response to dopamimetric drugs, one year follow up, and long term response to L-DOPA treatment. Spiperone binding was assayed using ten different concentrations (0.03–3 nmol) in absence or presence of 1μmol (+)-butaclamol to determine nonsepecific binding. There was no significant difference in spiperone binding between patients with PD not treated with L-DOPA, and patients with other basal ganglia disorders including parkinsonian syndrome due to vascular lesions, multiple system atrophy, or progressive supranuclear palsy, and age matched controls. Binding was significantly higher in parkinsonian patients with PD treated with L-DOPA and patients with essential tremor. It is concluded that at present3H-spiperone binding gives no further information in the differential diagnosis of de novo Parkinson's disease.
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  • 8
    ISSN: 1435-1463
    Keywords: Keywords: Immunocytochemistry ; dopaminergic neuron ; neurotrophin ; transplantation.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary. We investigated the expression of BDNF and its high affinity receptor trkB in fetal dopaminergic grafts in a rat model of Parkinson's disease. Grafts were allowed to differentiate for 7, 14, 28, or 56 days, respectively and were analyzed immunocytochemically thereafter with antibodies directed against tyrosine hydroxylase, BDNF and trkB. At all time points investigated, grafts contained tyrosine hydroxylase immunoreactive neurons. Immature grafts (7 days) displayed no immunoreactivity for BDNF which was restricted to glial cells at the graft-host interface. After longer differentiation periods BDNF-immunoreactivity was detectable in neurons and astrocytes within the grafts. No trkB immunoreactivity was found in immature grafts but a strong signal for trkB emerged in grafted neurons older than 14 days whereas glial cells remained unlabeled at all time points investigated. Expression of BDNF and trkB in grafted neurons and of BDNF in sourrounding glial cells suggests an autocrine or paracrine action of BDNF on dopaminergic neurons possibly mediated by activated glia.
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  • 9
    ISSN: 1433-0407
    Keywords: Schlüsselwörter M. Parkinson ; Ökonomie ; Krankheitskosten ; Motorische Komplikationen ; Key words Parkinson’s disease ; Cost of illness ; Motor fluctuations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Parkinson’s disease (PD) causes significant expense for the national health care system due to its chronic progressive course, the duration of the disease, the high prevalence and the devastating prognosis. In Germany more than DM 320 million are spent for drugs to alleviate parkinsonian symptoms. The aim of this study was to calculate the economic burden of PD by assessing direct medical costs. Forty patients suffering from idiopathic PD were interviewed at an office of neurological specialists and at an outpatient movement disorder clinic about their use of health care resources 3 months prior to the study. The total annual costs reported were DM 14,500, consisting of DM 6500 for drug therapy and DM 8000 for other medical services, including hospital inpatient care (DM 5600), outpatient care (DM 700), medical sundries (DM 1100) and physiotherapy (DM 600). The costs were positively correlated to the extent of the disease (Hoehn and Yahr stage; HY) and the occurrence of motor fluctuations/dyskinesias.We found that both drug-therapy expenses and total medical costs doubled from HYI to HYIV. The rarely employed s.c. therapy with apomorphine additionally increased the costs of drug therapy in HYV. The occurrence of fluctuations/ dyskinesias also increased medical expenses by approximately a factor of two. Indirect burden due to increased days off of work, unemployment and earlier retirement are also significant in Parkinson’s disease. This study oncludes that a treatment which could prevent or retard disease progression as well as a treatment that delays or reduces motor complications would not only ameliorate the situation of patients suffering from PD, but would also lead to significant reductions in cost for the national health care system.
    Notes: Zusammenfassung Die Parkinson-Erkrankung verursacht beträchtliche Ausgaben für das Gesundheits- und Sozialwesen. Allein in Deutschland werden Arzneimittel mit einem Volumen von ca. DM 320 Mio. für die Behandlung der Parkinson-Erkrankung verschrieben. Ziel dieser Studie mit 40 Patienten mit der Diagnose eines M. Parkinson aus Praxen niedergelassener Neurologen und einer Spezialambulanz für Bewegungsstörungen war es, die Krankheitskosten anhand eines Patientenkolletivs zu berechnen. Die direkten medizinischen Ausgaben wurden anhand retrospektiver Daten, die mittels eines Fragebogens erhoben wurden, für 3 Monate vor Studieneinschluß berechnet. Die direkten medizinischen Kosten der Erkrankung beliefen sich insgesamt auf DM 14500 pro Jahr (DM 6500 für Medikamente, DM 8000 für Leistungen, wie Krankenhausaufenthalt (DM 5600), ärztliche Leistungen (DM 700), Hilfsmittel (DM 1100) und Krankengymnastik (DM 600)). Die medikamentösen sowie die nichtmedikamentösen Kosten zeigten eine direkte Abhängigkeit vom Krankheitsstadium nach Hoehn und Yahr (HY). Die Kosten für Medikamente verdoppelten sich vom HY-Stadium I zum Hoehn-und-Yahr-Stadium IV. Insbesondere die Therapie mit Apomorphin führte in den späten Krankheitsstadien (HY V) zu einer erheblichen Verteuerung der medikamentösen Kosten. Das Auftreten von Fluktuationen und Dyskinesien hatte ebenfalls eine deutliche Zunahme der Ausgaben zur Folge; hier war die Behandlung um den Faktor 2 teurer als bei Patienten ohne Fluktuationen. Indirekte Kosten durch Arbeitsausfall und Frühverrentung sind als weitere wichtige Kostenfaktoren beim M. Parkinson anzusehen. Der Einhalt bzw. die Verlangsamung der Progression der Erkrankung oder die Verzögerung von motorischen Komplikationen würden nicht nur eine deutliche Verbesserung für die Behandlung von Parkinson-Patienten zur Folge haben, sondern wären auch von signifikanter ökonomischer Relevanz für die Gesellschaft und das Gesundheitssystem.
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  • 10
    ISSN: 1432-1106
    Keywords: Neural grafting ; Neural transplantation ; Parkinson's disease ; Cryopreservation ; Fetal mesencephalon ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study we quantitatively assessed to what extent freeze-storage at liquid nitrogen temperature influences the survival and function of fetal mesencephalic grafts in the dopamine-depleted rat striatum. Ventral mesencephalic (VM) tissue was dissected from rat fetuses and stored overnight in a preservative medium at 4 °C (hibernation). It was grafted intrastriatally either as a fresh cell suspension or was frozen as tissue fragments or as a cell suspension after stepwise incubation in ascending concentrations of dimethyl-sulphoxide. Following a cryopreservation interval of 80 days in liquid nitrogen, the frozen samples were rapidly thawed, rinsed, and grafted. Cellular viabilities of graft cell suspensions, as assessed by ethidium bromide/acridine orange staining, were decreased from 90% in fresh tissue to 38-35% in frozen and thawed tissue. Amphetamine-induced turning behavior at 6 weeks post-grafting was significantly attenuated in hosts that had received fresh grafts or grafts that were frozen as tissue fragments. Tyrosine hydroxylase-(TH-) immunocytochemistry of recipient brains revealed significant decreases in TH-positive graft cell numbers in rats grafted with cryopreserved tissue (38–42% of fresh tissue). Moreover, the dye exclusion viability of thawed VM tissue was found to accurately predict the subsequent graft survival. There was no difference with respect to graft cell numbers between the two freezing methods employed, though block storage seems to be more simple from a practical point of view. The present study indicates that freezing in liquid nitrogen may be a feasible method for long-term storage of fetal neural tissue for grafting, although a marked decrease in graft survival and function of cryopreserved tissue must be taken into account.
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