Biomedical subjects

T N Chase

Publications and source records attributed to T N Chase.

At least 163 records · Page 9Linked to original sources

PubMed1991

L-dopa does not affect electron transfer chain enzymes and respiration of rat muscle mitochondria.

Alterations in mitochondrial respiratory chain enzymes have been found in skeletal muscle of parkinsonian patients. Most of these patients had received treatment with L-dopa in combination with an inhibitor of peripheral decarboxylase for several years. In order to determine whether these effects are only dependent on the disease or are partially due to its therapy, the effects of L-dopa methyl ester and benserazide, a peripheral dopa decarboxylase inhibitor, were studied on various parameters related to energy metabolism in rat skeletal muscle mitochondria. The maximum activities related to complexes of the respiratory chain: rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, cytochrome c oxidase, state 3, state 4, uncoupled state, and respiratory control ratio were measured after 17-19 days of treatment. The results indicate that L-dopa treatment does not interfere with any of the parameters investigated and suggest that changes in muscle mitochondrial function found in parkinsonian patients are the result of the disease process and not its treatment.

Animals↗

PubMed1991

Striatal D1 dopamine receptor morphochemistry following continuous or intermittent L-dopa replacement therapy.

Striatal dopamine deafferentation has previously been found to diminish D1 dopamine receptor clustering in association with striatal cyclic AMP-immunoreactive neurons. The administration of the dopamine precursor levodopa (L-DOPA) to animals with unilaterally placed 6-hydroxydopamine nigrostriatal tract lesions now appears to partially restore D1 dopamine receptor morphochemical organization in the deafferented striatum. Differences in the mode of levodopa delivery produced dissimilar D1 recovery patterns. The prodrug, L-DOPA methyl ester, was administered in combination with the peripheral aromatic amino acid decarboxylase inhibitor, benserazide, to achieve consistent plasma levels of the dopamine precursor. Continuous levodopa infusion (100 mg/kg/day, ip) led to a slight dorsomedial reassociation of D1 receptor binding sites with the postsynaptic cyclic AMP transduction system on the deafferented side. In contrast, intermittent levodopa therapy (50 mg/kg, ip, bid) produced a noticeable down regulation of the dopamine receptor system and also contributed to some region-specific recovery of the morphochemical pattern of D1 receptor binding site reaggregation with the postsynaptic cyclic AMP second messenger transduction system. These results suggest that exogenous levodopa replacement therapy desensitizes striatal D1 dopamine receptors. This was substantiated using image analysis of densitometric histograms. The down regulation of D1 receptors is dependent on the levodopa treatment regimen employed. Our findings provide a potential morphological basis for the behavioral desensitization shown previously in response to chronic, intermittent levodopa administration.

Animals↗

PubMed1991

Differential memory and executive functions in demented patients with Parkinson's and Alzheimer's disease.

Selected aspects of verbal memory and executive function were compared in 11 demented Parkinson's disease (PD) patients and 11 Alzheimer's disease (AD) patients with equally severe dementia, with 11 healthy controls matched for age and education. Semantic and episodic memory were impared in all patients compared with controls, but to a relatively greater degree in AD patients than in those with PD. In contrast, demented PD patients were relatively more compromised on executive tasks. These findings, taken in the context of the neuropathological and neurochemical overlap between demented PD and AD patients, suggest that differences in neurobehavioural patterns in patients with these diseases are relative, rather than absolute.

Aged↗

PubMed1991

Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson's disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.

Antiparkinson Agents↗

PubMed1991

Cerebrospinal fluid acetylcholinesterase in progressive supranuclear palsy: reduced activity relative to normal subjects and lack of inhibition by oral physostigmine.

Acetylcholinesterase (AChE) activity was measured in lumbar cerebrospinal fluid (CSF) of 11 patients with progressive supranuclear palsy (PSP) and 18 age-matched healthy control subjects. Mean CSF AChE activity in PSP subjects was significantly reduced by 31% relative to control subjects (p less than 0.002). In the light of evidence of a central cholinergic deficit, physostigmine was administered orally (0.5-2.0 mg every two hours, six times a day for 10 days) to eight of the 11 PSP patients. CSF was sampled when the patients were on placebo and when receiving physostigmine and CSF AChE and butyrylcholinesterase (BChE) activities were measured. There was no significant change in either CSF AChE or BChE activities following physostigmine treatment. These data suggest that the doses of physostigmine used were insufficient to produce marked inhibition of AChE within the central nervous system.

Acetylcholinesterase↗

PubMed1991

Nootropic drugs in Alzheimer's disease: symptomatic treatment with pramiracetam.

The cognitive-enhancing effects of pramiracetam in animal models of learning and memory are characterized by an inverted U-shaped dose-response curve. We evaluated antidementia efficacy of this drug in 10 patients with probable Alzheimer's disease employing a 2-phase, placebo-controlled, enrichment-type trial design. Eight patients evidenced a best dose in the dose-finding phase, but in the subsequent replication phase only two again improved to a similar degree. PETs with fluorodeoxyglucose obtained in two individuals showed no definite change. Doses up to 4,000 mg pramiracetam are unlikely to confer symptomatic benefit to Alzheimer's disease patients.

Aged↗

PubMed1991

Clinical trials in dementia: learning effects with repeated testing.

The possible confounding role of learning effects during multiple test administration in clinical trials in demented subjects remains uncertain. Seventeen mildly to severely affected patients with Alzheimer's disease (AD) and 16 controls were evaluated with an extensive neuropsychological battery of manually administered and computerized tests. Subjects received 3 weekly sessions using alternate test forms, to mimic a baseline, placebo, and drug condition. Mean scores of AD patients as a group showed no stable improvement, but more subtle learning effects were suggested by an association of dementia severity and change scores in verbal and visual learning. Controls evidenced consistent learning in 3 of 9 tests. These results suggest that clinical trials data from AD patients, especially those with moderately severe impairment, are not contaminated by learning. Degree of cognitive impairment may be related to learning capacity, suggesting caution for learning effects in controls and possibly in patients with mild AD.

Aged↗

PubMed1990

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.

The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.

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

PubMed1990

Responses of substantia nigra pars reticulata neurons to GABA and SKF 38393 in 6-hydroxydopamine-lesioned rats are differentially affected by continuous and intermittent levodopa administration.

Systemic administration of the selective D1 agonist, SKF 38393, to rats with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine pathway induces contralateral turning and reduces firing rates of substantia nigra pars reticulata neurons. Previous studies have shown that chronically administered levodopa diminishes the contralateral turning induced by SKF 38393 in these animals. The present study demonstrates that twice daily injections (45-50 mg/kg, i.p.) of levodopa for 19 days also diminishes the effects of SKF 38393 on substantia nigra pars reticulata activity. Concomitant with this change, chronic levodopa injections reversed the lesion-induced supersensitivity of substantia nigra pars reticulata neurons to iontophoresed GABA. Neither of these effects were produced by the continuous infusion of levodopa (90-100 mg/kg/day, i.p. by osmotic pump) for 19 days, a treatment that produces average daily blood levodopa levels similar to those produced by chronic levodopa injection. These results suggest that large variations in circulating levodopa levels in 6-hydroxydopamine lesioned rats may desensitize the behavioral responses to D1 dopamine agonist administration by down-regulating D1 and GABA receptor-mediated mechanisms of basal ganglia output through the substantia nigra pars reticulata.

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

PubMed1990

Frontal lobe function in progressive supranuclear palsy.

Performance on tasks evaluating "executive and attentional" processes presumably subserved by prefrontal cortex were compared in patients with progressive supranuclear palsy and with age- and education-matched control subjects. The results indicated that patients with progressive supranuclear palsy were particularly impaired when a task required sequential movements, conceptual shifting, monitoring the frequency with which stimuli are presented, or rapid retrieval of verbal knowledge. These deficits could not simply be accounted for by slowed information processing or by a deficit in representational knowledge. Conceivably, "weak activation" of frontal lobe representational knowledge characterized by an observed attentional deficit results in the neuropsychological impairments noted in patients with progressive supranuclear palsy. The oral administration of physostigmine, under double-blind placebo-controlled conditions, did not facilitate executive or attentional performance as evaluated by our tasks.

Affect↗

PubMed1990

Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease.

The management of fluctuations in motor function complicating advanced Parkinson's disease with continuously administered dopaminomimetics was studied in 12 patients. In response to 7 to 12 days of round-the-clock intravenous infusions of levodopa, fluctuations in motor performance gradually diminished, ultimately by more than 40%. The beneficial effect persisted for about 6 days after withdrawal of continuous parenteral treatment and resumption of standard oral therapy. Clinical improvement was associated with changes in several pharmacological indices: Acute dose-response studies of intravenous levodopa showed a shift of the curve to the right in the immediate postinfusion phase compared to preinfusion studies; the therapeutic index improved significantly as patients demonstrated about 76% increased beneficial antiparkinsonian response with an equal degree of toxic dyskinetic effects; and the duration of action of levodopa was prolonged by 30%. These results suggest that changes in central dopaminergic mechanisms contributing to motor complications in advanced Parkinson's disease can be modified by procedures that provide continuous dopamine replacement. Presumably these modifications underlie the gradual amelioration of motor fluctuations over several days of round-the-clock therapy. Results of the present study also suggest potential deleterious effects of chronic intermittent oral treatment in the development of motor complications and thus support the role of long-term, continuous administration of dopaminomimetics.

Aged↗

PubMed1990

Effect of chronic D-1 and/or D-2 dopamine antagonist treatment on SKF 38393-induced non-stereotyped grooming.

The effects of chronic D-1 and/or D-2 dopamine (DA) receptor blockade on a putative D-1 DA receptor-mediated behavioral function was studied in rats treated for 21 days with the selective D-1 antagonist SCH 23390, the predominantly D-2 antagonist haloperidol, or the combination of both drugs at the same daily doses. Four days after the last drug dose, the non-stereotyped grooming response to the selective D-1 agonist SKF 38393 increased in SCH 23390-pretreated rats decreased in haloperidol-pretreated rats compared to controls, but remained unchanged in animals receiving both drugs. Underlying DA receptor changes and the resulting imbalance between D-1 and D-2 receptor presumably contribute to these effects, suggesting that the upregulation of one DA receptor subtype may modify the expression of behaviors associated with the other subtype.

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

PubMed1990

The effects of striatal lesion on turning behavior and globus pallidus single unit response to dopamine agonist administration.

In normal rats, globus pallidus neurons are excited by the systemic administration of postsynaptically active doses of apomorphine. The role of the striatum in mediating this phenomenon was examined by investigating the effects of apomorphine on neuronal activity in the globus pallidus and on turning behavior in rats with unilateral quinolinic acid lesions of the striatum. The lesion markedly reduced striatal choline acetyltransferase activity and GABA content and significantly attenuated apomorphine's effect on the activity of pallidal neurons. Both the extent of attenuation of the electrophysiological response of pallidal neurons in lesioned animals and the neurotoxin-induced decreases in choline acetyltransferase activity and GABA content in the caudal striatum were correlated with the degree of apomorphine-induced turning. The data indicate that striatopallidal neurons contribute to apomorphine's excitatory effect on the activity of pallidal neurons in normal animals.

Animals↗

PubMed1990

Dopamine D1 receptor modulation of pilocarpine-induced convulsions.

The contribution of dopaminergic mechanisms to the generalization of epileptic activity was studied in rats given pilocarpine after pretreatment with selective dopamine agonists. At the dose of 200 mg/kg, pilocarpine produced limbic stereotypes but not convulsions or seizure-related brain damage. Pilocarpine, 200 mg/kg, following pretreatment with the D1 agonist (RS)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3 benzazepine, but not its (S)-enantiomer, induced convulsive activity as revealed by behavioral, electroencephalographic alterations and widespread brain damage. These features were identical to those produced by a higher, convulsant dose of pilocarpine (400 mg/kg). On the other hand, pretreatment with the D2 agonist 4,4a,5,6,7,8,8a,9-octahydro-5-n-propyl-2H-pyrazolo-3,4-g-quinoline failed to induce convulsions. Furthermore, the D1 receptor antagonist (R)-(+)-8-chloro-2,3,4,5-n-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine -7-ol prevented the convulsive activity induced by both 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3 benzazepine plus pilocarpine (200 mg/kg) and pilocarpine (400 mg/kg), given alone. However, neither dopamine agonists nor antagonists altered the limbic stereotypes induced by pilocarpine, suggesting a dopamine system involvement primarily in the mechanisms of epilepsy generalization. The results suggest that pharmacological manipulation of dopaminergic transmission may provide an alternative approach to therapy of secondarily generalized epilepsy.

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

PubMed1990

Selective deficits in Alzheimer and parkinsonian dementia: visuospatial function.

Deficits in visuospatial cognition are frequently cited as an important component of the cognitive changes accompanying Parkinson's disease. To characterize possible differences between Parkinson's (PD) and Alzheimer's (AD) dementia, patients from both groups, matched for overall dementia severity, age and education, were contrasted neuropsychologically. Visuospatial tasks dissociated from memory, were significantly compromised in both patient groups. Differential impairment was evident on visuospatial abstraction and reasoning (Object Assembly), which was most deficient in PD. Visuospatial cognition associated with memory, classified both patient groups as impaired compared to controls, but AD patients demonstrated substantially lower performance levels than those with PD. Parkinsonian dementia thus appears to have some distinct features compared to Alzheimer's disease, which may indicate differences in underlying pathogenic mechanisms.

Adult↗

PubMed1990

Impairment of central auditory function in Alzheimer's disease.

Accuracy and laterality of ear preference on dichotic listening (DL) takes were compared in patients with Alzheimer's disease (AD) and a group of normal subjects, matched for age and education, using parameters (list length, stimulus matching, and order of recall), previously shown to significantly alter DL performance in normals. Alzheimer patients tended to show qualitatively similar, but significantly worse performance compared to controls as a function of increasing dichotic list length as well as stimulus set content (semantically, v. phonemically and unmatched dichotic items). Furthermore, these patients were unable to attend selectively to either the right- or left-ear and thus could not increase right- or left-ear advantages over the free recall procedure, an order of recall task easily mastered by the normal subjects. These results suggest that Alzheimer's disease is associated with a breakdown of cortical mechanisms involved in the selective allocation of attention.

Aged↗

PubMed1990

Selective deficits in cognition and memory in high-functioning parkinsonian patients.

To evaluate the profile and extent of cognitive deficits in Parkinson's disease, afflicted patients of exceptional professional distinction, who continue to function successfully in leadership positions, were compared neuropsychologically to neurologically normal individuals, matched for sex, age, education and professional standing. While patients showed relative preservation of verbal skills and higher executive function, they exhibited a significant reduction in episodic memory and visuospatial function. The observation of circumscribed impairment in this select group of Parkinsonian patients further implicates cognitive and memory deficits as consistent features of Parkinson's disease.

Adult↗

PubMed1990

Chronic levodopa treatment alters basal and dopamine agonist-stimulated cerebral glucose utilization.

The effect of chronic levodopa administration on the functional activity of the basal ganglia and its output regions was evaluated by means of the 2-deoxyglucose (2-DG) autoradiographic technique in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The rates of local cerebral glucose utilization were studied under basal conditions as well as in response to challenge with a selective D1 or D2 dopamine-receptor agonist. Levodopa (100 mg/kg/d, i.p.) was administered for 19 d either continuously via infusion with an osmotic pump or intermittently by twice-daily injections. Following a 3-d washout, glucose utilization was found to be decreased by both levodopa regimens in the nucleus accumbens; intermittent levodopa also decreased glucose utilization in the entopeduncular nucleus, subthalamic nucleus, ventrolateral thalamus, ventromedial thalamus, ventroposterolateral thalamus, and lateral habenula. In control (lesioned and treated chronically with saline) rats, the D1 agonist SKF 38393 (5 mg/kg, i.v.) increased 2-DG uptake in the substantia nigra pars reticulata and entopeduncular nucleus ipsilateral to the lesion by 84% and 56%, respectively. Both continuous and intermittent levodopa blunted the SKF 38393-induced elevation in glucose metabolism in the substantia nigra pars reticulata, while intermittent levodopa also attenuated the increase in the entopeduncular nucleus. The D2 agonist quinpirole (0.4 mg/kg, i.v.) did not increase glucose utilization in any brain region in control animals; following intermittent levodopa treatment, however, quinpirole increased 2-DG uptake by 64% in the subthalamic nucleus and by 39% in the deep layers of the superior colliculus on the ipsilateral side.(ABSTRACT TRUNCATED AT 250 WORDS)

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