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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 19 recordsLinked to original sources
PubMed1992

Striatal neuropeptide levels in Parkinson's disease patients.

Substance P (SP), Met-enkephalin (Met-enk) and cholecystokinin-8-S (CCK-8-S) were measured by a combined HPLC/RIA method in the caudate nucleus and anterior putamen from controls and from Parkinson's disease (PD) patients. SP levels were reduced in caudate in PD, but unchanged in putamen. No differences in Met-enk content were found in parkinsonians compared to controls. However, a significant correlation between DA and Met-enk levels in caudate nucleus from PD was observed. The concentration of CCK-8-S was unaltered in caudate nucleus or putamen in PD. The decrease in caudate nucleus SP levels might be related to the decrease in nigral SP levels in PD, while the reduction in Met-enk levels appears to be a feature of a subgroup of parkinsonian patients.

Aged↗
PubMed1992

Transplantation of embryonic mesencephalic and medullary raphe neurons to the neostriatum of rats with unilateral 6-hydroxydopamine lesions.

The implantation of dopamine-rich mesencephalic grafts into the 6-hydroxydopamine (6-OHDA)-lesioned neostriatum of rats was accompanied by marked hyperinnervation by serotonin (5-HT) fibers. The purpose of this study was to examine the possibility that the graft-derived 5-HT hyperinnervation is governed by target-related effects present in the host neostriatum and the question of whether grafts rich in 5-HT cells can ameliorate the drug-induced motor asymmetry resulting from unilateral 6-OHDA lesions. Rats were allocated to one of two groups: lesion plus mesencephalic raphe grafts (group R5-HT/L); and lesion plus medullary raphe grafts (group C5-HT/L). A third group, sham-lesion plus mesencephalic raphe grafts (group R5-HT/S) was included. Complete recovery of (+)-amphetamine-induced rotation was observed only in rats which received 5-HT grafts derived from medullary raphe neurons. There was no marked recovery of apomorphine-induced rotation in either of the R5-HT/L and C5-HT/L groups. Immunohistochemistry showed that the R5-HT/L and C5-HT/L groups had 5-HT hyperinnervation in the neostriatum of the lesioned side. There was no target-related effect of the 6-OHDA-lesioned neostriatum specific for the different types of 5-HT tissue. It seems likely that the 5-HT tissue derived from the medullary raphe may contain additional neurotransmitters which contribute to the behavioral recovery.

Amphetamine↗
PubMed1992

Effects of a unilateral 6-hydroxydopamine lesion and prolonged L-3,4-dihydroxyphenylalanine treatment on peptidergic systems in rat basal ganglia.

The effect of a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle or of a sham lesion on the neuropeptide content of the striatum and substantia nigra was investigated with or without 6 months L-3,4-dihydroxyphenylalanine (L-DOPA; 200 mg/kg per day) plus carbidopa (25 mg/kg per day) treatment. [Met5]- and [Leu5]enkephalin, substance P (SP), neurotensin (NT) and cholecystokinin (CCK) were measured by a combined HPLC/RIA method. Neurotensin levels were increased in the striatum, and [Leu5]enkephalin, and SP levels were reduced in the substantia nigra as a consequence of the lesion, while the levels of other peptides were unaltered. Administration of L-DOPA to sham-operated rats bilaterally increased SP levels in striatum and substantia nigra, and [Met5]enkephalin and CCK content in substantia nigra. L-DOPA treatment of 6-OHDA-lesioned rats increased [Met5]- and [Leu5]enkephalin and CCK levels in the striatum ipsilateral to the lesion but not on the intact side. In the substantia nigra, the lesion-induced decrease in [Leu5]enkephalin and SP was reversed by L-DOPA treatment, [Met5]enkephalin and CCK levels ipsilateral to the lesion were further enhanced, and there was an increase in NT ipsilateral to the lesion. Cryptic [Met5]- and [Leu5]enkephalin increased in the ipsilateral striatum following an 6-OHDA lesion. L-DOPA treatment did not alter cryptic enkephalin levels or the lesion-induced increase in cryptic [Met5]enkephalin, while cryptic [Leu5]enkephalin was further increased in lesioned animals given L-DOPA. These results suggest that the pattern of change in basal ganglia peptides in Parkinson's disease is not due solely to the destruction of the nigrostriatal pathway, the drug treatment of the disease or a combination of these factors.

Animals↗
PubMed1992

Growth hormone response to clonidine in central and peripheral primary autonomic failure.

Patients with primary autonomic failure may have either pure autonomic failure (PAF) or multiple system atrophy (MSA) in which there is additional neurological involvement. Distinction between PAF and MSA at an early stage is important because a wide range of complications is associated with MSA, which has a poor response to drug therapy and a less favourable prognosis. We have investigated the growth hormone (GH) releasing effects of clonidine in patients with PAF and MSA to see whether this hormonal response could serve as a neuroendocrine marker to distinguish between the groups. Age-matched normal subjects were studied as controls. Both groups of patients had severe postural hypotension due to primary sympathetic failure of presumed central origin in MSA and peripheral origin in PAF. After clonidine, plasma GH concentrations increased in controls and PAF, with no change in MSA. Changes in plasma glucose and insulin concentrations were similar in all groups. Clonidine, therefore, stimulates growth hormone release in PAF but not MSA and may serve as a neuroendocrine marker in differentiating patients with MSA and a central autonomic defect from those with PAF with a peripheral defect.

Adult↗
PubMed1992

Dissociation of the striatal D-2 dopamine receptor from adenylyl cyclase following 6-hydroxydopamine-induced denervation.

Intracellular cyclic AMP accumulation following exposure to dopamine (DA) agonists and and antagonists was measured in striatal slices from rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and which showed contralateral circling to apomorphine. Both DA (10-320 microM) and the D-1 agonist SKF 38393 (0.1-32 microM) increased cyclic AMP accumulation in striatal slices from the lesioned and intact hemispheres. The EC50 for DA to increase cyclic AMP accumulation in slices was greater in the 6-OHDA-lesioned striata compared to the intact striatum, but the EC50 for SKF 38393 was not affected. The D-1 antagonist SCH 23390 (10 microM) completely inhibited the ability of DA and SKF 38393 to increase cyclic AMP accumulation in striatal slices from both denervated and intact sides of the brain. In slices from the intact hemisphere the increase in DA-induced cyclic AMP accumulation was enhanced by the D-2 antagonist (+/-)-sulpiride (50 microM) but (+/-)-sulpiride had no effect on the DA response in slices from the lesioned side. Similarly, the ability of SKF 38393 to enhance cyclic AMP accumulation was blocked by the D-2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere but not in tissue from the lesioned side. The density of striatal D-1 and D-2 receptors assessed by [3H]SCH 23390 and [3H]spiperone binding did not differ between the hemispheres although there was an increase in the affinity of D-1 receptors for [3H]SCH 23390 in the lesioned striatum. After striatal deafferentiation there appears to be an uncoupling of the "inhibitory" D-2 receptor from the D-1 receptor-associated adenylyl cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Acute reserpine treatment induces down regulation of D-1 dopamine receptor associated adenylyl cyclase activity in rat striatum.

Behavioural studies suggest a functional interaction between D-1 and D-2 systems in normal rat striatum to alter motor behaviour and which is disrupted by dopamine depletion induced by acute reserpine treatment. Consequently, we have investigated the effect of acute reserpine treatment on the biochemical interaction between D-1 and D-2 receptors present in rat striatal slices. Twenty-four hours following the administration of reserpine (5 mg/kg i.p.), striatal dopamine content was depleted by more than 73%; the density (B(max)) of D-1 receptor sites measured by the in vitro binding of [3H]SCH 23390 to striatal membranes was increased while the binding of [3H]spiperone to D-2 receptor sites was unaltered. Reserpine treatment had no effect on the affinity (Kd) of [3H]SCH 23390 or [3H]spiperone for D-1 and D-2 sites. Basal levels of cyclic AMP accumulation in striatal slices prepared from reserpine-treated rats were lower than those observed in control slices. In striatal slices prepared from normal rats, dopamine (10-320 microM) and the D-1 agonist SKF 38393 (0.1-3.2 microM) induced concentration-dependent increases in cyclic AMP accumulation. The D-1 antagonist SCH 23390 (10 microM) abolished the accumulation of cyclic AMP produced by dopamine or SKF 38393. The D-2 antagonist (+/-)-sulpiride (50 microM) enhanced the response to dopamine (10-320 microM) while the D-2 agonist quinpirole (10 microM) abolished the response to SKF 38393 (0.1-3.2 microM). However, 24 hr after reserpine treatment the ability of dopamine (10-320 microM) and SKF 38393 (0.1-3.2 microM) to elicit an increase in cyclic AMP accumulation was markedly reduced in striatal slices. SCH 23390 (10 microM) did not enhance the trend for an increase in cyclic AMP accumulation produced by dopamine. Also, quinpirole (10 microM) did not affect the response to SKF 38393 (0.1-3.2 microM) in striatal slices from reserpine pretreated rats. The data confirm the positive linkage between D-1 receptors and adenylyl cyclase and the inhibitory coupling to D-2 sites in striatal slices from normal, rats. Acute reserpine treatment appears to cause an uncoupling of D-1 receptors associated with adenylyl cyclase.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Autoradiographic study of striatal D1 and D2 dopamine receptors in 6-OHDA-lesioned rats receiving foetal ventral mesencephalic grafts and chronic treatment with L-dopa and carbidopa.

Foetal dopamine cell suspensions or sham preparations were implanted into the denervated striatum of rats with a unilateral 6-hydroxy-dopamine (6-OHDA) lesion of the medial forebrain bundle. Some animals were also treated with L-DOPA (200 mg/kg/24 h) and carbidopa (25 mg/kg/24 h) in the drinking water for 5 weeks, followed by a 3-week drug-free period. Rotational responses to apomorphine and (+)-amphetamine were assessed, and the density of D1 and D2 dopamine receptors was evaluated autoradiographically in striatal slices exposed to [3H]SCH 23390 or [3H]spiperone. Foetal grafts reduces apomorphine-induced contralateral rotation and prevented the development of apomorphine-induced stereotypy. Foetal grafts abolished (+)-amphetamine-induced ipsilateral rotation. These effects of the grafts were not altered by treatment with L-DOPA. A unilateral 6-OHDA lesion of the nigrostriatal pathway resulted in an ipsilateral increase in D2 receptor density most marked in the lateral and dorsomedial quadrants of the striatum compared with the contralateral side. Foetal ventral mesencephalic grafts implanted into the lesioned striatum decreased D2 receptor density to levels found in the contralateral intact striatum. Chronic L-DOPA and carbidopa treatment did not alter the effect of the grafts. A 6-OHDA lesion resulted in a reduction of D1 receptor density in the lateral areas of the lesioned striatum at Level 2. The presence of a foetal ventral mesencephalic graft either alone or together with L-DOPA treatment did not alter the lesion-induced changes in D1 binding density.

Animals↗
PubMed1992

Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Transplantation of fetal dopamine neurons in Parkinson's disease: PET [18F]6-L-fluorodopa studies in two patients with putaminal implants.

Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and [18F]6-L-fluorodopa ([18F]dopa). The uptake of [18F]dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen [18F]dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, [18F]dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of [18F]dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of [18F]dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which, balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C-raclopride and positron emission tomography.

Equilibrium striatal: cerebellar 11C-raclopride (RAC) uptake ratios reflect the density of striatal dopamine D2 binding sites. Using positron emission tomographic scanning we have measured striatal RAC uptake in 6 untreated patients with Parkinson's disease (PD), 5 chronically treated patients with PD and a fluctuating response to L-dopa, 10 patients with striatonigral degeneration (SND), and 9 patients with progressive supranuclear palsy (PSP). Regional cerebral blood flow was determined also, with C15O2. Mean striatal: cerebellar RAC uptake was not significantly different from normal in untreated patients with PD, though 2 of these 6 patients showed significantly increased putamen tracer binding. Mean caudate and putamen: cerebellar RAC uptake ratios of the group with PD and a fluctuating response to L-dopa were significantly reduced by 30% and 18%, respectively. The patients with SND had lesser, but significant, 10% and 11% decreases in mean caudate and putamen: cerebellar RAC uptake ratios, respectively, whereas patients with PSP showed 24% and 9% reductions in caudate and putamen: cerebellar RAC binding. Striatal and frontal blood flow were significantly reduced in patients with PSP, but not in patients with PD or SND. In conclusion, striatal D2 binding potential is normal or raised in untreated patients with PD, but reduced in patients with PD and a fluctuating response to L-dopa. Patients with SND and PSP show a decrease in striatal RAC binding, but to a lesser extent than patients with PD and a fluctuating response to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

A follow-up study of isolated cases of suspected Huntington's disease.

We reviewed 49 patients in whom a diagnosis of Huntington's disease (HD) seemed possible on clinical grounds, but who gave no history of definitely affected relatives. In 32 with the typical clinical features of HD (progressive chorea and dementia, postural instability, abnormal initiation of saccadic eye movements), the diagnosis was confirmed in 7 patients who had had autopsies, affected relatives were found in 5 others, and HD remained probable in a further 13 who were reexamined. In the 17 with a less typical clinical picture, a diagnosis of HD appeared most likely in 2; other causes for chorea such as cerebrovascular disease, neuroacanthocytosis, recrudescence of Sydenham's chorea, and drug-induced tardive dyskinesia could be invoked in the remainder. We conclude that the likelihood of HD in a patient with the typical clinical features of this disorder but no history of affected relatives is at least 75%, which for practical purposes implies a risk to their children hardly less than in familial HD. The most plausible explanations for seemingly sporadic patients with HD are nonpaternity and mild, late-onset disease that is overlooked by other family members.

Adult↗
PubMed1992

"Resetting" of postural tremors at the wrist with mechanical stretches in Parkinson's disease, essential tremor, and normal subjects mimicking tremor.

The response of postural wrist tremors to brief mechanical displacements was compared in two groups of patients, one with classical hereditary essential tremor (n = 18) and another with typical Parkinson's disease (n = 13). These groups were compared with an additional group of normal subjects mimicking wrist tremor (n = 9). The degree to which brief mechanical displacements of the wrist produced by torque pulses of three different sizes could modulate the timing of rhythmic electromyographic bursts in the forearm flexor muscles was quantified by deriving a resetting index, which could range between 0 (no phase resetting) and 1 (complete phase resetting). In all three groups of subjects studied, the resetting index varied significantly with the size of the mechanical perturbation and, in an inverse fashion, with the ongoing tremor amplitude. When due allowance for these factors was made, the difference in mean resetting indexes between the three groups of patients and subjects was reduced to the extent that no definitive statement could be made as to whether brief mechanical perturbations had more effect on essential tremor than parkinsonian tremor. The method is therefore unlikely to be useful in differentiating the common causes of postural wrist tremors.

Adult↗
PubMed1992

Dystonia induced by combined treatment with L-dopa and MK-801 in parkinsonian monkeys.

We examined whether the N-methyl-D-aspartate antagonist MK-801 (dizocilpine) would reverse parkinsonism or potentiate the effects of L-dopa in primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to its effect in rodent models, treatment with MK-801 (0.1 mg/kg) caused bradykinesia and ataxia in parkinsonian primates, but no locomotor stimulation. Coadministration of MK-801 (0.1 mg/kg) with L-dopa (20 mg/kg) induced marked dystonia accompanied by bradykinesia and ataxia. Dystonia was not induced by either treatment given alone. These findings indicate that MK-801 should not be advocated as an adjunct to dopamine agonist therapy in Parkinson's disease.

Animals↗
PubMed1992

Alpha-tocopherol levels in brain are not altered in Parkinson's disease.

alpha-Tocopherol (vitamin E) levels in normal brain were lower in the cerebellum than in the cerebral cortex or basal ganglia. There was no difference in alpha-tocopherol levels in the cerebellum, basal ganglia, or cerebral cortex between control subjects and patients with Parkinson's disease.

Aged↗
PubMed1992

Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group.

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group.

We examine the evidence for free radical involvement and oxidative stress in the pathological process underlying Parkinson's disease, from postmortem brain tissue. The concept of free radical involvement is supported by enhanced basal lipid peroxidation in substantia nigra in patients with Parkinson's disease, demonstrated by increased levels of malondialdehyde and lipid hydroperoxides. The activity of many of the protective mechanisms against oxidative stress does not seem to be significantly altered in the nigra in Parkinson's disease. Thus, activities of catalase and glutathione peroxidase are more or less unchanged, as are concentrations of vitamin C and vitamin E. The activity of mitochondrial superoxide dismutase and the levels of the antioxidant ion zinc are, however, increased, which may reflect oxidative stress in substantia nigra. Levels of reduced glutathione are decreased in nigra in Parkinson's disease; this decrease does not occur in other brain areas or in other neurodegenerative illnesses affecting this brain region (i.e., multiple system atrophy, progressive supranuclear palsy). Altered glutathione metabolism may prevent inactivation of hydrogen peroxide and enhance formation of toxic hydroxyl radicals. In brain material from patients with incidental Lewy body disease (presymptomatic Parkinson's disease), there is no evidence for alterations in iron metabolism and no significant change in mitochondrial complex I function. The levels of reduced glutathione in substantia nigra, however, are reduced to the same extent as in advanced Parkinson's disease. These data suggest that changes in glutathione function are an early component of the pathological process of Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Death↗
PubMed1992

Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia. The Royal Kings and Queens Parkinson's Disease Research Group.

Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

Basal Ganglia Diseases↗