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Biomedical subjects

K W Lange

Publications and source records attributed to K W Lange.

At least 19 recordsLinked to original sources
PubMed1992

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease.

Reduced and oxidized glutathione concentrations in post-mortem brain tissue from the substantia nigra of control subjects and patients with neuropathologically confirmed Parkinson's disease were measured by a coulometric method using high-pressure liquid chromatography and electrochemical detection. Reduced glutathione concentrations were decreased in the substantia nigra of parkinsonian patients compared with controls. Differences in the concentration of oxidized glutathione and in the percentage of oxidized glutathione of the total glutathione were not observed between parkinsonian and control subjects. The finding that oxidized glutathione is not decreased in Parkinson's disease suggests that the decrease in reduced glutathione is not exclusively the consequence of neuronal loss in the substantia nigra but may indicate a state of oxidative stress.

Aged↗
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

Brain muscarinic cholinergic receptors in Huntington's disease.

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Brain Chemistry↗
PubMed1992

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction.

A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication. Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention. More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired. Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure. Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication. Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning. Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests. The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning.

Brain Diseases↗
PubMed1992

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to MPTP-treated common marmosets.

The ability of selective D-1 agonist and antagonist drugs to alter motor deficits and locomotor activity was studied in MPTP-treated common marmosets. Both the D-2 agonist quinpirole and the mixed D-1/D-2 agonist apomorphine reversed the motor impairments and induced locomotor activity. The D-1 antagonist SCH 23390 and the D-2 antagonist raclopride given alone further reduced motor function in MPTP-treated animals. The actions of quinpirole were potently and completely inhibited by raclopride but only partially and inconsistently by SCH 23390. In contrast, the effects of apomorphine were markedly but incompletely inhibited by both raclopride and SCH 23390. The D-1 agonist SKF 38393 alone caused a dose related reduction in motor activity. SKF 38393 weakly and partially inhibited the improvements in motor function produced by quinpirole but had a more pronounced effect on apomorphine induced motor activity. The induction of motor activity in MPTP treated common marmosets may separately involve both D-1 and D-2 receptors. Comparison with our previous data on the effect of the same drugs in normal common marmosets provides some evidence for a breakdown of linkage between D-1 and D-2 systems following MPTP treatment. The actions of SKF 38393 in MPTP-treated common marmosets contrasts with its ability to induce behavioural activation and a facilitation of D-2 mediated behaviour in rodents. SKF 38393 may not be the compound with which to delineate the role of D-1 receptors in primates.

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

Cognitive performance in multiple system atrophy.

The cognitive performance of a group of patients with multiple system atrophy (MSA) of striato-nigral predominance was compared with that of age and IQ matched control subjects, using three tests sensitive to frontal lobe dysfunction and a battery sensitive to memory and learning deficits in Parkinson's disease and dementia of the Alzheimer type. The MSA group showed significant deficits in all three of the tests previously shown to be sensitive to frontal lobe dysfunction. Thus, a significant proportion of patients from the MSA group failed an attentional set-shifting test, specifically at the stage when an extra-dimensional shift was required. They were also impaired in a subject-ordered test of spatial working memory. The MSA group showed deficits mostly confined to measures of speed of thinking, rather than accuracy, on the Tower of London task. These deficits were seen in the absence of consistent impairments in language or visual perception. Moreover, the MSA group showed no significant deficits in tests of spatial and pattern recognition previously shown to be sensitive to patients early in the course of probable Alzheimer's disease and only a few patients exhibited impairment on the Warrington Recognition Memory Test. There were impairments on other tests of visual memory and learning relative to matched controls, but these could not easily be related to fundamental deficits of memory or learning. Thus, on a matching-to-sample task the patients were impaired at simultaneous but not delayed matching to sample, whereas difficulties in a pattern-location learning task were more evident at its initial, easier stages. The MSA group showed no consistent evidence of intellectual deterioration as assessed from their performance on subtests of the Wechsler Adult Intelligence Scale (WAIS) and the National Adult Reading Test (NART). Consideration of individual cases showed that there was some heterogeneity in the pattern of deficits in the MSA group, with one patient showing no impairment, even in the face of considerable physical disability. The results show a distinctive pattern of cognitive deficits, unlike those previously seen using the same tests in patients with Parkinson's and Alzheimer's diseases, and suggesting a prominent frontal-lobe-like component. The implications for concepts of 'subcortical' dementia and 'fronto-striatal' cognitive dysfunction are considered.

Adult↗
PubMed1992

Fronto-striatal cognitive deficits at different stages of Parkinson's disease.

Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the 'Tower of London' test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and 'early in the course' of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage. These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's disease.

Aged↗
PubMed1992

Epilepsy and criminal law.

Automatic episodes of aggressive or violent behaviour may occur during or after an epileptic fit. Epileptic automatisms are regarded by the law as 'insane automatisms'. A person who commits a crime during the course of a seizure is therefore legally insane and must be committed to a psychiatric hospital. The law of insanity is inappropriate when applied to epileptic automatisms. A change in the law is therefore necessary to remove epileptic offenders from the legal ambit of insanity, and to save them the threat of detention in a mental hospital as a consequence of their crime.

Aggression↗
PubMed1992

Glutamatergic-dopaminergic balance in the brain. Its importance in motor disorders and schizophrenia.

Dopamine appears to be of less importance in the regulation of psychomotor functions than was previously thought. A central dopaminergic-glutamatergic balance may be important for both akinetic motor disorders and psychosis. In Parkinson's disease glutamate antagonists may counteract central glutamatergic hyperactivity and may be of value as anti-parkinsonian drugs. An increase of dopaminergic activity and/or a reduction of glutamatergic activity may contribute to the development of paranoid hallucinatory psychosis in schizophrenic patients and of pharmacotoxic psychosis in Parkinson's disease. Because of possibly severe side-effects of glutamatergic antagonists and agonists in the treatment of akinesia and psychosis, the development of partial glutamate agonists/antagonists could be an alternative strategy capable of producing antipsychotic or anti-kinetic effects with only mild adverse reaction.

Animals↗
PubMed1992

Neurotoxicity and neuroprotection in Parkinson's disease.

Recent findings of impaired mitochondrial function, altered iron metabolism and increased lipid peroxidation in the substantia nigra in Parkinson's disease emphasize the significance of oxidative stress and free radical formation in the pathogenesis of the disease. Future research will focus on improvements in neuroprotective therapy to prevent or slow the rate of progression of Parkinson's disease. Possible neuroprotective strategies include free radical scavengers, monoamine oxidase-B inhibitors, iron chelators and glutamate antagonists.

Antiparkinson Agents↗
PubMed1992

Pathogenesis of Parkinson's disease.

The importance of genetic aspects, ageing, environmental factors, head trauma, defective mitochondrial respiration, altered iron metabolism, oxidative stress and glutamatergic overactivity of the basal ganglia in the pathogenesis of Parkinson's disease (PD) are considered in this review.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Glutamate receptor antagonism: neurotoxicity, anti-akinetic effects, and psychosis.

There is evidence to suggest that glutamate and other excitatory amino acids play an important role in the regulation of neuronal excitation. Glutamate receptor stimulation leads to a non-physiological increase of intracellular free Ca2+. Disturbed Ca2+ homeostasis and subsequent radical formation may be decisive factors in the pathogenesis of neurodegenerative diseases. Decreased glutamatergic activity appears to contribute to paranoid hallucinatory psychosis in schizophrenia and pharmacotoxic psychosis in Parkinson's disease. It has been suggested that a loss of glutamatergic function causes dopaminergic over-activity. Imbalances of glutamatergic and dopaminergic systems in different brain regions may result in anti-akinetic effects or the occurrence of psychosis. The simplified hypothesis of a glutamatergic-dopaminergic (im)-balance may lead to a better understanding of motor behaviour and psychosis.

Animals↗
PubMed1991

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets.

In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apomorphine, were weakly inhibited by SCH 23390. The selective D-1 partial agonist SKF 38393 decreased motor activity and did not induce grooming, oral movements or other behaviours. SKF 38393 inhibited motor activity induced by the administration of quinpirole but did not alter apomorphine-induced motor behaviour. Locomotor activity in normal common marmosets appears to be mediated mainly via D-2 systems. In contrast to rodents, administration of SKF 38393 does not induce behavioural activation and there does not appear to be a facilitating effect of D-1 systems on D-2 function in the normal common marmoset. However, the ability of both SKF 38393 and SCH 23390 to inhibit quinpirole locomotor activity suggests some interaction between D-1 and D-2 systems to occur in this species.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-dopa in models of Parkinson's disease.

Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

[Narcolepsy].

Explore the source record for details and available documents.

Adolescent↗
PubMed1990

Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP+ administration.

Unilateral intranigral injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ (1-methyl-4-phenylpyridine) were given to young rats and unilateral intranigral injections of MPTP were given to old rats. MPTP in old rats and MPP+ in young rats induced ipsiversive circling for at least one week after injection and contraversive circling after the systemic administration of apomorphine; the number of D-2 receptors (Bmax) in the striatum of the injected hemisphere increased compared with that of control rats. MPTP in young rats induced only short-lasting ipsiversive circling and no contraversive circling after apomorphine; the number of striatal D-2 receptors did not increase. These results suggest that the neurotoxicity of MPTP is age-dependent in the rat, and that MPTP has neurotoxic effects on the nigrostriatal dopaminergic system in old rats and induces dopamine receptor supersensitivity in the denervated striatum.

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