Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 559 records · Page 31Linked to original sources

PubMed1987

Age-related decreases in the concentration of Met- and Leu-enkephalin and neurotensin in the basal ganglia of rats.

Previous studies using radioimmunoassay procedures have failed to show age-related changes in the concentration of Met- and Leu-enkephalin or neurotensin in rat basal ganglia. In contrast, using a combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) technique we now report considerable decreases in the levels of these neuropeptides in areas of basal ganglia of 22 months old-compared to 3 months-old male Wistar rats. The concentration of Met-enkephalin was greatly reduced in the striatum and nucleus accumbens, but not in substantia nigra, of old compared to young animals. There was a similarly large decrease in Leu-enkephalin content in striatum of old rats with less marked decreases occurring in both the nucleus accumbens and substantia nigra. Neurotensin levels in the striatum and substantia nigra were greatly reduced in old rats, with a less marked decrease in the nucleus accumbens.

Aging↗

PubMed1987

The significance of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The chance occurrence of an outbreak of persistent parkinsonism amongst young drug addicts abusing a synthetic pethidine derivative has aroused considerable interest. The offending agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has to be converted by monoamine oxidase B perhaps in glia, into the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). MPP+ is then taken up into dopaminergic neurons by the normal dopamine re-uptake system. Once within dopaminergic neurons it binds to neuromelanin, so is retained to kill nerve cells, perhaps by generation of free radicals and other toxic species. MPTP produces parkinsonism in primates (but not in many lower species, probably because they possess little or no neuromelanin). MPTP toxicity in primates can be prevented by treatment with monoamine oxidase inhibitors, or by inhibitors of dopamine re-uptake, and to some extent by antioxidants. Toxicity of MPTP is remarkably selective. It preferentially destroys the substantia nigra pars compacta, but may spare the adjacent pigmented ventral tegmental areas, as well as other neuronal systems. However, selectivity decreases with age: MPTP causes more widespread damage in older animals. Affected individuals exhibit all symptoms and signs of Parkinson's disease. As well as providing an accurate animal model of the illness, MPTP is one of the first environmental neurotoxins known to cause parkinsonism in humans. This observation has led to reappraisal of the epidemiology of the illness and a search for similar environmental agents. Understanding the mechanism of MPTP toxicity has also provided suggestions on how to treat the cause of Parkinson's disease.

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

PubMed1987

What do the basal ganglia tell premotor cortical areas?

The defects in execution of simple single arm movements at one joint, and of complex arm movements simultaneously or sequentially at two joints, in Parkinson's disease are analysed as a clue to the formal functions of the basal ganglia in human motor control. Slowness in execution of single movements, due to failure to scale the size of the initial electromyographic burst of activity in the agonist, is one characteristic abnormality. However, patients with Parkinson's disease are also shown to have added difficulty with complex motor tasks. When they attempt to undertake a hand 'squeeze' at the same time as an elbow 'flex', both movements are even slower. When they try to perform an elbow flex as quickly as possible after a hand squeeze with the same or opposite arms, the second movement is slowed and the interval between movements is prolonged. Similar movement abnormalities have been found in patients with Huntington's disease-even in those with chorea alone, and irrespective of drug therapy-and in a patient with an infarct involving the right supplementary motor area. These observations suggest that the basal ganglia in humans are required to set up the correct motor programmes to execute complex simultaneous and sequential movements. It is suggested that the basal ganglia, acting on a read-out of existing sensorimotor cortical activity, direct the premotor cortical areas to select the correct parameters of the motor programmes required for subsequent motor action.

Arm↗

PubMed1987

Examination of motor function in lesions of the spinal cord by stimulation of the motor cortex.

Electrical stimulation of the motor cortex was performed in 3 patients with cervical cord trauma and in 3 with cervical myelopathy caused by cervical spondylosis. Abnormal conduction in central motor tracts was demonstrated in 5 of the 6 patients; yet in 4 of these, cortical somatosensory evoked potentials from the same limb were of normal latency. In the remaining patient who had normal motor latencies, the somatosensory evoked potentials were delayed on one side. Electrophysiological examination of the motor pathways by cortical stimulation may therefore be of considerable value in the assessment and management of patients with traumatic and compressive disease of the spinal cord.

Adult↗

PubMed1987

Gait disorder of subcortical arteriosclerotic encephalopathy: Binswanger's disease.

The abnormality of gait that may occur in patients with subcortical arteriosclerotic encephalopathy (Binswanger's disease) is described in 12 patients in whom difficulty walking was the presenting symptom. Their gaits had elements of both Parkinsonism and ataxia, which were most marked in 4 patients unable to stand unaided. The difficulty in using their legs to walk was out of proportion to that of other movements of the lower limbs when lying or seated. In contrast, upper limb mobility and facial expression were relatively preserved. Attention is drawn to the similarity of this gait pattern to that of some patients with hydrocephalus, frontal lobe lesions, and "senile" disorders of gait. A possible mechanism for this Parkinsonian-ataxia in these various conditions may be their propensity to damage the afferent and efferent interconnections of the leg areas of the motor and supplementary motor areas of the cerebral cortex with, the cerebellum and basal ganglia.

Aged↗

PubMed1987

Antiparkinsonian activity of (+)-PHNO in the MPTP-treated common marmoset.

Administration of MPTP (1-4 mg/kg ip daily for 5-7 days) to common marmosets induced persistent parkinsonian motor deficits. The subcutaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine; 1-4 micrograms/kg] caused a dose-dependent reversal of the akinesia and incoordination of movement. Similarly, oral administration of (+)-PHNO (5-20 micrograms/kg) caused an equivalent reversal of the motor abnormalities. No dyskinetic phenomena were induced by (+)-PHNO on oral or subcutaneous administration. Oral or subcutaneous administration of (+)-PHNO to normal control marmosets also increased the usual repetoire of motor behaviour, but this was not as marked as in MPTP-treated animals. (+)-PHNO is a potent dopamine agonist drug of potential use in the treatment of Parkinson's disease.

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

PubMed1987

Antiparkinsonian activity of a single oral dose of PHNO.

PHNO, a new D-2 agonist, was investigated in five patients with Parkinson's disease. In an acute, open, oral, dose-ranging study comparing benefit from single doses, 4 mg of PHNO was found to be equivalent to one tablet of Sinemet 25/250 mg. Adverse reactions were those anticipated for a dopaminomimetic agent. Because of its novel structure and apparent transcutaneous penetration, further studies on PHNO are desirable.

Administration, Oral↗

PubMed1987

Anticholinergic-induced chorea in the treatment of focal dystonia.

The occurrence of chorea, induced by trihexyphenidyl (benzhexol hydrochloride) during the treatment of five adult patients who had focal or segmental dystonia, is described. The dose at which chorea appeared ranged from 15 to 60 mg/day (mean 31.7 mg/day). All but one patient had developed common adverse effects of this drug (dry mouth, blurred vision, and confusion) at lower doses (mean 21.8 mg per day). There was an inverse relationship between the age of the patient and the dose of trihexyphenidyl at which chorea developed.

Adult↗

PubMed1987

Young onset Parkinson's disease.

We describe a personal series of 60 cases of parkinsonism with onset under the age of 40 years. Known causes for early onset of secondary parkinsonism, such as Wilson's disease or encephalitis, were excluded in every case. Two groups were identified: those with onset after the age of 21 in whom no hereditary factors could be ascertained (56 cases), and those with onset before 21 years all of whom had familial parkinsonism. In neither group have we found any association with prematurely grey hair, hypertension, diabetes, pernicious anaemia, or thyroid disorder. Among their families, we have not found any association with diabetes, pernicious anaemia, or thyroid disorder. We propose that cases of apparent idiopathic Parkinson's disease beginning between age 21-40 years should be called "young onset Parkinson's disease." Twenty percent of such patients in our series had at least one first- or second-degree relative in the same or antecedent generations with parkinsonism, but only 1.5% of their relatives at risk had parkinsonism, which is similar to the prevalence in the general population. Ten percent of these patients had at least one relative with essential tremor, but only 1.6% of their relatives at risk had tremor, which again was similar to the prevalence in the population in general. These patients with young onset Parkinson's disease responded well to levodopa therapy. However, dyskinesias and response fluctuations occurred early and frequently. The prevalence of dyskinesias and response fluctuations was strongly correlated with the duration of levodopa treatment, but not with the duration (or probably the severity) of the disease before levodopa therapy was commenced. The involuntary movements often were severe and frequently were diphasic. Despite long disease duration, the incidence of dementia in young onset patients aged less than 65 years was negligible. We believe that most, if not all, patients in this group have degenerative Lewy body idiopathic Parkinson's disease, representing the lower end of a skewed deviation for age of onset of this disease. We have so far failed to identify any additional environmental factor which may have accelerated disease onset in these patients. In contrast, cases of parkinsonism beginning before age 21 years were invariably familial. We proposed that they should be called "juvenile parkinsonism." All affected relatives with parkinsonism also had young disease onset, and all but one were siblings. None of four such patients seen by us has demented, and computed tomography (CT) scan has been normal in all four. We believe that most such patients have some form of genetically determined secondary parkinsonism.

Adult↗

PubMed1987

Dopamine and somatostatin modulated adenylate cyclase activity in the rat caudate-putamen following unilateral cortical ablation.

Dopamine and somatostatin-14 (SRIF) were incubated with a membrane fraction of rat caudate-putamen (CP) tissue in an adenylate cyclase assay in order to examine the D-1-receptor coupled adenylate cyclase activity 5 days and 3 weeks after unilateral ablation of the left frontal and lateral cortex. Five days after decortication the ipsilateral basal and dopamine stimulated adenylate cyclase activity was increased by about 30% compared to that of the contralateral side. Three weeks after decortication no significant difference could be seen. On either side basal and dopamine stimulated adenylate cyclase activity was not significantly decreased compared to sham operated controls. Somatostatin (10(-7) mol/l) reduced basal adenylate cyclase activity of the ipsilateral CP five days following lesioning and reduced the maximal stimulation induced by dopamine. The effects of somatostatin were most marked in the absence and at low concentrations of dopamine (10(-7)-10(-6) mol/l). The effects of somatostatin in the lesioned CP were no longer apparent three weeks following surgery. These results do not favour a presynaptic localization of D-1-receptors on cortico-striate projection fibers and suggest that somatostatin is involved in the interaction of the cortico-striate and nigro-striatal projection systems and may play a role in the regulation of D-1-receptor linked adenylate cyclase.

Adenylyl Cyclases↗

PubMed1987

Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine.

Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.

Animals↗

PubMed1987

The Bereitschaftspotential, L-DOPA and Parkinson's disease.

Bereitschaftspotentials (BPs) prior to extension movements of the index finger were studied in normal subjects and in patients with Parkinson's disease. In both, BPs were studied before and after L-DOPA therapy; in addition, the normal subjects were studied after dopamine antagonists. In both patients and normal subjects, L-DOPA caused an increase in the amplitude of the early part of the BP and of the point of peak negativity, just prior to EMG onset (N1) but it did not cause an increase of the late lateralized part of the BP (NS' of Shibasaki); in normal subjects dopaminergic antagonists caused a decrease in the amplitude of the N1. Control experiments suggested that the change caused by L-DOPA was not the result of slower movement or poorer triggering when OFF drugs. For patients with Parkinson's disease there was no correlation between the change in their peak BP negativity (N1) after L-DOPA and their change in clinical mobility; in addition, there was no difference in the peak BP negativity of patients OFF therapy and that of age-matched normals, though there was a slight decrease in the amplitude of the early part of the BP for the patients with Parkinson's disease; this was the same part that had been enlarged by L-DOPA therapy. These findings suggest that the N1 is not affected by Parkinson's disease and that the effect of dopaminergic drugs on the N1 is mediated by actions on dopaminergic mechanisms elsewhere than in the striatum, perhaps in the cerebral cortex itself. The effect of L-DOPA will need to be taken into account in subsequent studies of the BP in Parkinson's disease.

Adult↗

PubMed1987

The interpretation of electromyographic responses to electrical stimulation of the motor cortex in diseases of the upper motor neurone.

The complexities of interpreting results of electrical stimulation of the motor cortex in pathological states are discussed and illustrated by reference to results from a variety of patients with diseases affecting the upper motor neurone (multiple sclerosis, cervical spondylosis and myelopathy, motor neurone disease, hemiparesis due to cerebral infarction, and hereditary spastic paraplegia). The abnormalities of the electromyographic (EMG) responses after anodal cortical stimulation consisted of delay in the latency to onset, dispersion or reduction in response size or even absence of EMG responses. These changes were not confined to any specific condition or pathology. Previous work has suggested that the sequence of events that follow anodal cortical stimulation involves repetitive excitatory inputs to spinal motoneurones and transmission across at least one central synapse. Accordingly, delayed latencies may not exclusively indicate slowing of motor conduction, while the absence of any response may not indicate complete failure of conduction in corticomotoneurone pathways.

Adult↗

PubMed1987

Chronic pharmacological manipulation of dopamine receptors in brain.

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of L-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.

Acetylcholine↗

PubMed1987

In vitro characterisation of dopamine receptors in the superior colliculus of the rat.

In membrane preparations of superior colliculus of the rat, the binding of [3H]spiperone (0.15 nM) was displaced by the incorporation of (+)-butaclamol, haloperidol, apomorphine and (+/-)-sulpiride, but not by (-)-butaclamol, prazosin, propranolol, ketanserin or cinanserin. The Ki values for the displacement of [3H]spiperone by (+/-)-sulpiride, (+)-butaclamol and haloperidol were similar in tissue preparations from superior colliculus and striatum. Equilibrium analysis of the specific binding of [3H]spiperone (0.03-1.0 nM), defined by 10(-5) M (+/-)-sulpiride, to membrane preparations of the superior colliculus, showed the interaction to be saturable and of high affinity. However, the Bmax was only approximately 10% of that found in preparations of striatum; the apparent dissociation constant (KD) was the same in both preparations of the superior colliculus and striatum. Uptake of [3H]dopamine into synaptosomal preparations of the superior colliculus was approximately 20% of that found in synaptosomes from the striatum. In preparations of striatum nomifensine, but not desipramine or fluoxetine, inhibited the uptake of [3H]dopamine. However, in preparations from the superior colliculus, nomifensine, desipramine and fluoxetine were without effect on the uptake of [3H]dopamine. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were present in small concentrations in the superior colliculus. Homovanillic acid (HVA) was present in larger concentrations and the HVA plus DOPAC/dopamine ratios were greater in the superior colliculus than in the striatum. The superior colliculus contained only small amounts of noradrenaline but 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were present in larger amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Effects of continuous administration for 12 months of amine-depleting drugs and chlorpromazine on striatal dopamine function in the rat.

Rats received either chlorpromazine (33-36 mg/kg/day), oxypertine (6.3-7.3 mg/kg/day), tetrabenazine (6.0-6.7 mg/kg/day) or reserpine (0.28-0.30 mg/kg/day) continuously for up to 12 months. Chlorpromazine and tetrabenazine reduced spontaneous locomotor activity of animals after 1 month of treatment. Thereafter, locomotor activity in animals treated with chlorpromazine returned to control levels, whereas treatment with tetrabenazine increased locomotion. Oxypertine enhanced spontaneous locomotor activity after 9 months of administration only, whereas treatment with reserpine did not alter this activity at any time during the study compared to age-matched controls. Treatment with tetrabenazine enhanced stereotyped behaviour induced by apomorphine (0.063-1.0 mg/kg s.c.) throughout the study. In contrast, stereotypy in animals administered chlorpromazine, oxypertine or reserpine was the same as in control animals throughout the 12 months of treatment. Levels of dopamine in the striatum were reduced after the first month of administration of chlorpromazine, but thereafter returned to control values. Treatment with oxypertine for up to 12 months did not alter concentrations of dopamine in the striatum, whereas administration of tetrabenazine and reserpine caused a decrease. All treatments with drugs consistently reduced the content of homovanillic acid in the striatum during the study. The Bmax for specific binding of [3H]spiperone in the striatum was increased by continuous treatment of animals with chlorpromazine, oxypertine or tetrabenazine, although the effects of oxypertine and tetrabenazine were only transient. Administration of reserpine did not alter the Bmax for specific binding of [3H]spiperone. The Bmax for specific binding of [3H]piflutixol in the striatum was unchanged by any treatment for up to 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

An immunohistochemical study of the acute and long-term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset.

Administration of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces a parkinsonian syndrome in primates. Intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the common marmoset (Callithrix jacchus) produced symptoms of rigidity, akinesia and tremor which persisted for at least one month. However, after this time, considerable behavioural recovery occurred, although animals were still severely bradykinetic compared with controls. Marmosets were allowed to survive for 1, 3 1/2 or 7 months prior to histological and immunocytochemical analysis. Detection of catecholaminergic neurons using antibodies directed against the enzyme tyrosine hydroxylase revealed a profound (80%) loss of dopaminergic cells from the substantia nigra one month after initiation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. This was accompanied by a severe gliosis. Fewer cells were lost from the adjacent ventral tegmental area (45%), but dopamine-containing cells in other brain areas were not obviously affected. At longer survival times the substantia nigra was less damaged, with a proliferation of glia in the pars compacta and a loss of approximately 20% of the dopaminergic perikarya. Using immunohistochemical techniques, the distribution of neuropeptides substance P, [Met]enkephalin and dynorphin 1-17-like immunoreactivity were examined and found to exhibit distinctive patterns in the marmoset substantia nigra. The integrity of these systems appeared intact at all times after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. These results support the hypothesis that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces a clinical syndrome, indistinguishable from Parkinson's disease, via a selective destruction only of neurons with perikarya in the substantia nigra pars compacta and the ventral tegmental area. The findings that the peptidergic input to these cells together with most non-nigral dopaminergic cell groups are not damaged, indicate that the selectivity of the lesion produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine appears greater than that seen in idiopathic Parkinson's disease. The neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset may not be permanent since both behavioural and biochemical recovery were observed after several months.

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

PubMed1987

Mood swings associated with the 'on-off' phenomenon in Parkinson's disease.

Mood swings accompanying the motor fluctuations of patients with Parkinson's disease on chronic levodopa treatment frequently occur, but are poorly recognized. Occasionally, their functional impact may be greater than that caused by the motor disability itself. In this study we have assessed the nature of, and relationship between, mood and motor fluctuations in nine Parkinsonian patients with 'on-off' motor swings. The results of an additional questionnaire survey confirm that 'on-off' mood swings occur in approximately two thirds of patients with Parkinson's disease experiencing motor fluctuations on dopaminergic treatment. Aetiological and therapeutic implications are discussed.

Adult↗