Square-wave action dystonia in Parkinson's disease.
Explore the source record for details and available documents.
Antiparkinson Agents↗
Biomedical subjects
T N Chase
Publications and source records attributed to T N Chase.
A trial of dextromethorphan in parkinsonian patients with motor response complications.
The effects of the NMDA antagonist dextromethorphan (DM) on levodopa-associated dyskinesias and motor fluctuations were studied in patients with advanced Parkinson's disease. During initial open-label dose escalation, 6 of 18 patients reported a beneficial effect at their individually determined optimal DM dose (range, 60-120 mg/day). The 12 remaining patients either experienced reversible side effects, particularly mild drowsiness, or decreased levodopa efficacy, and were therefore excluded from the study. The six responders entered the double-blind, placebo-controlled, crossover study with two 2-week arms separated by 1 week wash-out. On the last day of each arm, motor ratings were performed every 20 minutes for 8 consecutive hours. In addition, motor complications and Activities of Daily Living (ADL) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and patient diaries. With DM, dyskinesias improved by 25% according to physician's ratings and by 40% according to UPDRS interviews, without compromising the anti-Parkinson effect of levodopa. Motor fluctuations and ADL scores also improved significantly. Although the narrow therapeutic index of DM limits its clinical usefulness, these findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate levodopa-associated motor complications.
Activities of Daily Living↗
Parkinson's disease: neurodegenerative mechanisms and neuroprotective interventions--report of a workshop.
Explore the source record for details and available documents.
Humans↗
Amantadine reduces levodopa-induced dyskinesias in parkinsonian monkeys.
The antidyskinetic potential of the glutamate NMDA receptor channel blocker amantadine was evaluated in four levodopa-primed parkinsonian monkeys using two different regimens (1.25 or 2.5 mg/kg administered subcutaneously twice daily for 3-6 days). When administered with a relatively low dose of levodopa, amantadine produced a near-total suppression of choreiform dyskinesias and a substantial reduction in dystonic dyskinesias at the expense of a significant reduction in antiparkinsonian response. With a high dose of levodopa, amantadine had a smaller but still significant effect on dyskinesias without altering the antiparkinsonian response. These results lend support to the view that glutamate receptor-mediated mechanisms contribute to levodopa-induced dyskinesias. They also suggest that amantadine could alleviate such complications in parkinsonian patients, especially with careful dose optimization.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavenger.
The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease.
In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.
Amantadine↗
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity.
Neuropsychological assessment of older individuals with dementing illnesses has suffered from a lack of appropriately designed test instruments. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was developed for the dual purposes of identifying and characterizing abnormal cognitive decline in the older adult and as a neuropsychological screening battery for younger patients. The entire battery takes less than 30 minutes to administer, and yields scaled scores for five cognitive domains. The current study reports preliminary clinical validity results with the RBANS, comparing very mildly demented patients with a diagnosis of probable Alzheimer's disease (n = 20) to patients with Huntington's disease (n = 20) and normal controls (n = 40). Although the patient groups had essentially identical total scores on the RBANS, they exhibited opposite profiles, differing significantly on four of the five subsections. The AD patients performed most poorly on Language, and Delayed Memory subsections, while the HD patients obtained their lowest scaled scores on the Attention and the Visuospatial/Constructional subsections. These results are consistent with the neuropsychological profiles of these dementing disorders derived from lengthier standardized tests and experimental investigations. In addition, even those patients who performed above the suggested cut-off points on the MMSE and the Dementia Rating Scale scored significantly below their controls on the RBANS. These data suggest that the RBANS is effective at both detecting and characterizing dementia of different etiologies.
Aged↗
Nuclear factor-kappa B contributes to excitotoxin-induced apoptosis in rat striatum.
Excitotoxin-induced destruction of striatal neurons, proposed as a model of Huntington's disease, involves a process having the biochemical stigmata of apoptosis. Recent studies suggested that transcription factor nuclear factor (NF)-kappa B may be involved in excitotoxicity. To further analyze the contribution of NF kappa B to excitotoxic neuronal death in vivo, changes in binding activities of NF kappa B and other transcription factors as well as the consequences of inhibiting NF kappa B nuclear translocation were measured after the infusion of quinolinic acid (120 nmol) into rat striatum. Internucleosomal DNA fragmentation and terminal transferase-mediated dUTP digoxigenin nick end labeling-positive nuclei appeared 12 hr later and intensified over the next 12 hr. NF kappa B binding activity increased several-fold from 2 to 12 hr, then gradually declined during the next 12 hr. Other transcription factor changes included AP-1, whose binding peaked about 6 hr after quinolinic acid administration, and E2F-1, which was only modestly and transiently elevated. In contrast, quinolinic acid lead to a reduction in OCT-1, beginning after 12 hr, and briefly in SP-1 binding. The NF kappa B, AP-1, and OCT-1 changes were attenuated both by the N-methyl-D-aspartate receptor antagonist MK-801 and the protein synthesis inhibitor cycloheximide. Moreover, quinolinic acid-induced internucleosomal DNA fragmentation and striatal cell death were significantly reduced by the intrastriatal administration of NF kappa B SN50, a cell-permeable recombinant peptide that blocks NF kappa B nuclear translocation. These results illustrate the complex temporal pattern of transcription factor change attending the apoptotic destruction produced in rat striatum by quinolinic acid. They further suggest that NF kappa B activation contributes to the excitotoxin-induced death of striatal neurons.
Animals↗
Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease.
OBJECTIVE: To determine the effects of the N-methyl-D-aspartate (NMDA) antagonist amantadine on levodopa-associated dyskinesias and motor fluctuations in Parkinson's disease (PD). BACKGROUND: NMDA receptor blockade can ameliorate levodopa-induced dyskinesias in primates and PD patients. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was recently found to possess NMDA antagonistic properties. METHODS: Eighteen patients with advanced PD participated in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week treatment arm, parkinsonian and dyskinesia scores were obtained during a steady-state intravenous levodopa infusion. Motor fluctuations and dyskinesias were also documented with patient-kept diaries and Unified Parkinson's Disease Rating Scale (UPDRS) interviews. RESULTS: In the 14 patients completing this trial, amantadine reduced dyskinesia severity by 60% (p = 0.001) compared to placebo, without altering the antiparkinsonian effect of levodopa. Motor fluctuations occurring with patients' regular oral levodopa regimen also improved according to UPDRS and patient-kept diaries. CONCLUSIONS: These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications.
Adult↗
Levodopa therapy: consequences of the nonphysiologic replacement of dopamine.
Normal motor function is dependent on the highly regulated synthesis and release of the transmitter dopamine by neurons projecting from the substantia nigra to the corpus striatum. Parkinson's disease involves the progressive degeneration of these neurons. Its core symptoms are a direct consequence of a striatal insufficiency of intrasynaptic dopamine. Levodopa, the standard of care for the treatment of PD, acts after its conversion to dopamine by restoring striatal dopaminergic transmission. However, there are significant differences between the normally functioning dopamine system and the restoration of function provided by standard levodopa treatment. Increasing clinical and preclinical evidence suggests that the intermittent stimulation of dopamine receptors resulting from current therapeutic regimens contributes to the response complications that ultimately affect most parkinsonian patients. It now appears that chronic nonphysiologic stimulation of dopaminergic receptors on striatal GABAergic neurons activates characteristic signaling pathways, leading to a potentiation of the synaptic efficacy of adjacent glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype. As a result, function of these GABAergic efferent neurons changes in ways that favor the appearance of motor complications. Conceivably, use of dopaminomimetic replacement strategies that provide more continuous dopamine receptor stimulation will act to prevent or alleviate these disabling complications. A number of promising approaches to achieving this goal are now under development.
Animals↗
Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease.
OBJECTIVE: This study assessed the effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson's disease (PD). BACKGROUND: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. METHODS: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief i.v. levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. RESULTS: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. CONCLUSIONS: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias.
Aged↗
Neostriatal mechanisms in Parkinson's disease.
Normal motor function is dependent on the highly regulated synthesis and release of dopamine (DA) by neurons projecting from substantia nigra to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) arise as a consequence of a deficiency in striatal DA due to the progressive degeneration of this neuronal system. Under such circumstances, the subunit composition and/or phosphorylation state of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the dendritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic transmission, significant differences exist between the normally functioning DA system and the restoration of function provided by standard levodopa therapy. The nonphysiologic stimulation of DA receptors on striatal spiny neurons associated with current levodopa regimens now appears to contribute to the motor response complications that ultimately affect most parkinsonian patients. Current evidence suggests that alterations in signaling systems linking dopaminergic and glutamatergic receptors within these GABAergic efferent neurons induce NMDA receptor modification. Functionally, the resultant long-term change in glutamatergic synaptic efficacy leads to alterations in spiny neuron output, favoring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimulation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transduction components or glutamate receptor sensitivity could ultimately prove safer and more effective for the treatment of all stages of PD.
Corpus Striatum↗
The significance of continuous dopaminergic stimulation in the treatment of Parkinson's disease.
Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements. Current evidence indicates that 'wearing-off' fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of 'wearing-off' phenomena as well as the eventual appearance of other response complications. Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the 'on-off' type and peak dose dyskinesias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson's disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.
Animals↗
Glutamate metabotropic receptor agonist 1S,3R-ACPD induces internucleosomal DNA fragmentation and cell death in rat striatum.
Glutamate metabotropic receptor mediated mechanisms have been implicated in both neuroprotection and neurotoxicity. To characterize these mechanisms further in vivo, the effects of an intrastriatally injected metabotropic receptor agonist, trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD), were studied alone and together with N-methyl-D-aspartate (NMDA) or kainic acid (KA) receptor agonists on DNA fragmentation and nerve cell death. 1S,3R-ACPD induced internucleosomal DNA fragmentation of striatal cells in a dose-dependent manner. TUNEL and propidium iodide staining showed DNA fragmentation and profound nuclear condensation around the injection site. Fragmented nuclei were occasionally seen under light microscopy. Internucleosomal DNA fragmentation induced by 1S,3R-ACPD was attenuated by the protein synthesis inhibitor cycloheximide as well as by the non-selective and selective metabotropic receptor antagonists L-(+)-2-amino-3-phosphonopionic acid (L-AP3), (RS)-aminoindan-1,5-dicarboxylic acid and (RS)-alpha-methylserine-o-phosphate monophenyl ester, respectively. The 1S,3R-ACPD (100-900 nmol) induced death of striatal neurons was suggested by the reduction in NMDA and D1 dopamine receptors by up to 13% (P < 0.05) and 20% (P < 0.05) as well as by the decline in GAD67 mRNA (25%, P < 0.01) and proenkephalin mRNA levels (35%, P < 0.01). Interestingly, 1S,3R-ACPD attenuated internucleosomal DNA fragmentation induced by NMDA, but potentiated that induced by KA. These results suggest that metabotropic receptor stimulation leads to the death of striatal neurons by a mechanism having the biochemical stigmata of apoptosis. Moreover, metabotropic receptor stimulation evidently exerts opposite effects on pre- or postsynaptic mechanisms contributing to the NMDA and KA-induced apoptotic-like death of these neurons.
Alanine↗
Protein kinase A inhibitor attenuates levodopa-induced motor response alterations in the hemi-parkinsonian rat.
Chronically administered levodopa, the standard treatment for Parkinson's disease, is ultimately associated with disabling alterations in motor response. To evaluate the possible contribution of striatal cAMP-dependent protein kinase A (PKA) signaling pathways to these response modifications, the acute effects of a PKA inhibitor, Rp-cAMPS, on motor response changes attending chronic, twice-daily administration of levodopa were measured in 6-hydroxydopamine lesioned hemi-parkinsonian rats. A single intrastriatal injection of Rp-cAMPS (2.5 or 25 microg) attenuated both the shortened duration and augmented intensity of levodopa-induced turning in a dose dependent manner. Rp-cAMPS completely normalized motor responses to a dopamine D1 agonist (SKF 38392), but had no effect on those to a dopamine D2 agonist (quinpirole). These results suggest that D1 receptor-mediated PKA activation may contribute to the development of the altered motor responses associated with chronic levodopa treatment.
Animals↗
A gene for Parkinson disease.
Until recently, the possibility that genetic factors contributed significantly to the pathogenesis of Parkinson disease (PD) was accorded relatively short shift. Few patients with obviously familial PD are seen in common practice, and families with parkinsonism often present with rather atypical features. The discovery that the neurotoxin N-methyltetrahydropyridine (MPTP) rapidly induces an illness similar to sporadic PD added fuel to those arguing that environmental factors must be largely responsible. But more recently, this view has begun to shift because no generally plausible environmental factors emerged and data favoring a genetic component began to mount. Now it is clear that the cause of PD may on occasion be purely genetic and involve autosomal dominant as well as various other inheritance patterns. Moreover, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects some combination of genetic susceptibility and environmental insult. In such instances, the genetic component presumably acts by increasing the vulnerability of dopamine-containing neurons in the nigrostriatal system to injury by 1 or more common, possibly by themselves relatively innocuous, environmental factors. This view has now been substantially reinforced and our ability to understand the pathogenesis of PD dramatically advanced by the recent identification of a gene responsible for PD in 4 unrelated families.
Environment↗
Gene therapy for Parkinson's disease: an approach to the prevention or palliation of levodopa-associated motor complications.
Gene therapy holds considerable potential for the treatment of central nervous system disease. The introduction of functional genes into the brain of patients with Parkinson's disease may, for example, prove useful as a means to replace a defective gene, introduce a potentially neuroprotective or neurorestorative protein, or permit the physiological delivery of a deficient neurotransmitter. Recent observations suggest that the oral administration of currently available dopaminomimetics to relatively advanced parkinsonian patients leads to nonphysiologic intermittent stimulation of striatal neurons that express dopamine receptors. Resultant activation of signal transduction pathways from these dopaminergic receptors on medium-sized GABAergic neurons apparently induces long-term potentiation of adjacent glutamatergic receptors of the N-methyl-D-aspartate subtype. The effects of dopaminergic drugs thus become modified in ways that favor the clinical appearance of response fluctuations and peak-dose dyskinesias. In parkinsonian models was well as in patients with Parkinson's disease, continuous dopaminergic replacement tends to prevent or alleviate these adverse effects. By continuously maintaining appropriate cerebral dopamine concentrations, molecular techniques which stimulate an increase in the intrastriatal activity of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, might be expected to palliate parkinsonian symptoms with less risk of the disabling consequences of current therapy. Clinical study of these approaches could also serve as initial, relatively simple, proof-of-principle evaluations of the safety and efficacy of genetic approaches to the treatment of basic disease processes in Parkinson's disease and related neurodegenerative disorders.
Dyskinesia, Drug-Induced↗
Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease.
The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-D-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that NMDA receptor blockade can counteract levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primates and parkinsonian patients without substantially altering the motor benefit derived from levodopa. These results appear to be in accordance with our 2-deoxyglucose studies in 6-hydroxydopamine-lesioned rats showing that NMDA receptor blockade can attenuate many of the changes in synaptic activity induced by levodopa, particularly in the striatopallidal complex. Taken together, our observations suggest that abnormal glutamate transmission or dysregulation of NMDA receptor-mediated mechanisms contribute to levodopa-induced motor response complications. Additional preclinical and clinical experiments need to be completed with well tolerated glutamate antagonists to determine the full potential of glutamate receptor blockade as a long-term strategy against levodopa-related motor response complications in Parkinson's disease.
Animals↗