Parkinson's disease: levodopa-induced dyskinesia and signal transduction

l-3,4-Dihydroxyphenylalanine (L-dopa) remains the most effective pharmacological treatment for relief of the severe motor impairments of Parkinson's disease. It is very effective in controlling parkinsonian symptoms in the initial phase of the disease, but its action wanes with time. Such 'wearing-off' imposes an escalation in the dosage of the drug, which ultimately fails to provide stable control of motor symptoms and results in the appearance of abnormal involuntary movements or dyskinesia. 'Peak-dose'l-dopa-induced dyskinesia (LID) currently represents one of the major challenges in the treatment of Parkinson's disease. Accumulating evidence suggests that LID derives from overstimulation of dopamine receptors located on the GABAergic medium spiny neurons (MSNs) of the dorsal striatum. These neurons form two distinct projection pathways, which exert opposite effects on motor activity: the direct, striatonigral pathway promotes locomotion, whereas the indirect, striatopallidal pathway depresses locomotion. In order to understand the mechanisms underlying LID, it is important to identify molecular adaptations produced by chronic administration of L-dopa, at the level of one or the other of these two neuronal populations. This review summarizes the results of recent studies indicating that LID is associated with abnormal dopamine D1 receptor signaling affecting the MSNs of the direct pathway. The role of this pathological adaptation and of the consequent changes in signaling in the development and expression of LID are discussed.     

Striatal proteomic analysis suggests that first L-dopa dose equates to chronic exposure

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it.     

Evidence for L-dopa incorporation into cell proteins in patients treated with levodopa

Levodopa (L-dopa) is the most widely used agent for the symptomatic relief of Parkinson's disease. There is concern that chronic L-dopa treatment may be detrimental, with some studies suggesting that L-dopa may be neurotoxic. A potentially important mechanism whereby L-dopa may exert neurotoxic effects has been overlooked: that of the incorporation of L-dopa into proteins by protein synthesis. L-Dopa competes with tyrosine as a substrate in protein synthesis in vitro. We provide evidence that L-dopa can also be incorporated into proteins in vivo. Blood from L-dopa-treated and -non-treated patients was separated into protein, erythrocyte and lymphocyte fractions and levels of protein-incorporated dopa quantified by HPLC. Levels of protein-incorporated dopa were significantly increased in lymphocyte cell proteins from L-dopa-treated patients. This has not arisen from oxidative pathways as there was no evidence of oxidative damage to proteins. In addition, there was no increase in protein-incorporated dopa in erythrocytes, which are not actively synthesizing proteins. We suggest that protein-incorporated dopa could also be generated in the CNS. The accumulation of protein-incorporated dopa in cells is associated with oxidative stress and impaired function and could contribute to some of the problems associated with long-term L-dopa treatment.     

Dopamine receptors and transporters in Parkinson's disease and schizophrenia

The loss of midbrain dopamine in Parkinson's disease is accompanied by a matching loss in the dopamine transporter and a rise in the D1 and D2 receptor densities. This is found in the brain putamen and caudate tissues from unmedicated patients, and may account for the good early clinical response to L-dopa. Long-term L-dopa treatment reverts the receptor densities toward normal levels. Positron emission tomography (PET) data and in vitro data generally concur. In schizophrenia the density of the dopamine transporter as well as that of the D1 dopamine receptor is normal. The D2 receptor density, however, is consistently elevated in postmortem brain putamen and caudate nucleus, even in tissues from neuroleptic-free or drug-naive patients. Three sets of PET and single photon emission computed tomography (SPECT) data support the postmortem findings. Early evidence indicating abnormal D2 structure as well as a reduced link between D1 and D2 warrant a detailed study of the genes for these two receptors in schizophrenia.     

Gene therapy for Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder arising from loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent depletion of striatal dopamine levels, which results in distressing motor symptoms. The current standard pharmacological treatment for PD is direct replacement of dopamine by treatment with its precursor, levodopa (L-dopa). However, this does not significantly alter disease progression and might contribute to the ongoing pathology. Several features of PD make this disease one of the most promising targets for clinical gene therapy of any neurological disease. The confinement of the major pathology to a compact, localised neuronal population and the anatomy of the basal ganglia circuitry mean that global gene transfer is not required and there are well-defined sites for gene transfer. The multifactorial aetiology of idiopathic PD means that it is unlikely any single gene will cure the disease, and as a result at least three separate gene-transfer strategies are currently being pursued: transfer of genes for enzymes involved in dopamine production; transfer of genes for growth factors involved in dopaminergic cell survival and regeneration; and transfer of genes to reset neuronal circuitry by switching cellular phenotype. The merits of these strategies are discussed here, along with remaining hurdles that might impede transfer of gene therapy technology to the clinic as a treatment for PD.     

Recognition and treatment of response fluctuations in Parkinson's disease: review article

Summary.  Patients with Parkinson's disease (PD) by definition benefit from treatment with the dopamine precursor levodopa. However, after 5 years of therapy 50% of patients experience motor response complications (MRC's): the benefit from each dose becomes shorter (wearing-off fluctuations), more unpredictable (on-off fluctuations) and associated with involuntary movements (dyskinesias). In addition these patients suffer from fluctuations in motor function that are inherent to the disease itself. Recent findings have lead to the suggestion that hyperfunction of NMDA receptors on striatal efferent neurons, as a consequence of chronic non-physiologic dopaminergic stimulation, contributes to the pathogenesis of MRC's. In PD patients blockade of striatal glutamate receptors with several NMDA-antagonists improve MRC's. With progression of PD the severity and complexity of MRC's magnify, obfuscating their pattern and their relation to the medication cycle. Only through detailed history taking and patient education will the physician be able to clarify the situation and establish a rational, targeted approach to the treatment of patients with advanced PD complicated by motor fluctuations and dyskinesias. Received July 7, 2001 Accepted August 6, 2001 Published online September 10, 2002     

The effects of L-dopa on the activity of methionine adenosyltransferase: Relevance to L-dopa therapy and tolerance

L-dopa, the major treatment for Parkinson's disease (PD), depletes S-adenosyl-L-methionine (SAM). Since SAM causes PD-like symptoms in rodents, the decreased efficacy of chronic L-dopa administered to PD patients may result from a rebound increase in SAM via methionine adenosyl transferase (MAT), which produces SAM from methionine and ATP. This was tested by administering intraperitoneally saline, or L-dopa to mice and assaying for brain MAT activity. As compared to controls, L-dopa (100 mg/kg) treatments of 1 and 2 times per day for 4 days did not significantly increase MAT activity. However, treatments of 1 and 2 times per day for 4 and 8 days did significantly increase the activity of MAT by 21.38% and 28.37%, respectively. These results show that short interval, chronic L-dopa treatments significantly increases MAT activity, which increases the production of SAM. SAM may physiologically antagonize the effects of L-dopa and biochemically decrease the concentrations of L-dopa and dopamine. Thus, an increase in MAT may be related to the decreased efficacy of chronic L-dopa therapy in PD.     

High performance microbiological transformation of L-tyrosine to L-dopa by <Emphasis Type="Italic">Yarrowia lipolytica</Emphasis>NRRL-143

Background  

The 3,4-dihydroxy phenyl L-alanine (L-dopa) is a drug of choice for Parkinson's disease, controlling changes in energy metabolism enzymes of the myocardium following neurogenic injury. Aspergillus oryzae is commonly used for L-dopa production; however, potential improvements in ease of handling, growth rate and environmental impact have led to an interest in exploiting alternative yeasts. The two important elements required for L-dopa production are intracellular tyrosinases (thus pre-grown yeast cells are required for the transformation of L-tyrosine to L-dopa) and L-ascorbate, which acts as a reducing agent.     

Production of 3,4-dihydroxy L-phenylalanine by a newly isolated <Emphasis Type="Italic">Aspergillus niger</Emphasis> and parameter significance analysis by Plackett-Burman design

Background  

The amino acid derivative 3,4-dihydroxy L-phenylalanine (L-dopa) is gaining interest as a drug of choice for Parkinson's disease. Aspergillus oryzae is commonly used for L-dopa production; however, a slower growth rate and relatively lower tyrosinase activity of mycelia have led to an increasing interest in exploiting alternative fungal cultures. In the present investigation, we report on the microbiological transformation of L-tyrosine to L-dopa accomplished by a newly isolated filamentous fungus Aspergillus niger.     

L-dopa and dopamine enhance the formation of aggregates under proteasome inhibition in PC12 cells

The formation of inclusion bodies in dopaminergic neurons is associated with the pathogenesis of Parkinson's disease. In order to clarify the role of dopamine/L-dopa in the formation of protein aggregates, we investigated dopamine/L-dopa-related aggregation using an experimental inclusion model. The inhibition of tyrosine hydroxylase (TH) by alpha-methyltyrosine dramatically decreased MG132-induced aggregate formation. In addition, the inhibition of TH caused the upregulation of proteasomes in cultured cells and the dopamine/L-dopa induced non-enzymatic polymerization of ubiquitin. This inhibition did not affect cell viability. These results suggest that dopamine/L-dopa might enhance aggregate formation, and that intracellular aggregates may not be toxic to cells.     

Movement disorders in sleep: Parkinson's disease and restless legs syndrome.

In recent years, sleep abnormalities have increasingly been observed in patients with movement disorders. During sleep, most patients with Parkinson's disease also exhibit the movements characteristically seen during the wake period. Movement activity during sleep may impair sleep quality and lead to daytime sleepiness and reduced quality of life. Disordered REM sleep with enhanced muscle tone is common in patients with neurodegenerative disease, and may precede the clinically evident symptoms of Parkinson's disease by years. Sleep disorders in patients with Parkinson's disease are common, and require the application of individual treatment strategies. A further frequent disorder primarily classified as a sleep disorder (dyssomnia) is the restless legs syndrome (RLS), which is closely related to the nocturnal periodic limb movement disorder and affects up to 15% of the population. The present review focuses on nocturnal motor activity and sleep in Parkinson's disease and RLS.     

Dietary method for reducing fluctuations in Parkinson's disease

Motor fluctuations and non-response to carbidopa-levodopa (Sinemet) therapy are major problems in the long-term management of Parkinson's disease. Levodopa manipulation, addition of adjuvants, and drug holidays are often unsuccessful. Others have shown that the clinical state of stabilized Parkinsonians can be reversed with intravenous administration of large neutral amino acids. Reasoning that dietary protein might precipitate motor oscillations and non-response, a low-protein daytime diet (7 g) was offered to fifteen patients. Eighty-six percent of this sample demonstrated immediate sensitivity to Sinemet. While on a low-protein diet, patients' clinical function was predominantly choreatic. Eight patients required a 10-60 percent reduction in their daily levodopa dose in order to minimize this choreatic tendency. Discontinuation of adjuvants did not compromise motor independence. Conversely, while on a high-protein diet (160 g), patients were predominantly immobile with markedly elevated plasma amino acid and levodopa levels. Consequently, elimination of dietary protein from breakfast and lunch can offer an effective and easily modified method for the amelioration of motor fluctuations and non-response to Sinemet in Parkinson's disease during working hours.     

Lifestyle regularity measured by the social rhythm metric in Parkinson's disease

Parkinson's disease (PD) is a chronic progressive motor disorder that may present with a spectrum of symptoms and disease severity. Therapy is frequently associated with motor fluctuations and dyskinesias; therefore, monitoring of motor fluctuations and daily abilities is important for adequate management. The Social Rhythm Metric (SRM) is a diary-like questionnaire that quantifies the extent to which a person's life is regular vs. irregular on a daily basis with respect to event timing. Lifestyle regularity has been assessed by the SRM in other clinical situations. The aim of this study was to evaluate lifestyle regularity in a population with PD using the SRM and its relationship to clinical and therapeutic factors. Twenty-eight consecutive patients with PD and 14 control subjects were studied. Severity of motor dysfunction was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS). Depressive symptoms were assessed with the Montgomery Asberg Depressive Rating Scale (MADRS), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and subjective daytime sleepiness with the Epworth sleepiness scale. Daily lifestyle regularity was assessed by the SRM for 2 weeks. Patients with PD had lower SRM scores than controls, and those with motor fluctuations had even lower scores (p=0.04). Patients with motor fluctuations showed more clinical disability (p=0.01), a worse quality of sleep (p=0.02), and more depressive symptoms (p=0.02). SRM results were correlated with PSQI values (p=0.016). Our findings show that the regularity of daily activities as measured by the SRM is disorganized in patients with PD and that this irregularity is related to sleep quality.     

Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa

The effects of L-dopa on methylation process in the mouse brain were investigated. The study is based on recent findings that methylation may play an important role in Parkinson's disease (PD) and in the actions of L-dopa. The methyl donor, S-adenosylmethionine (SAM) and a product of SAM, methyl beta-carboline, were shown to cause PD-like symptoms, when injected into the brain of animals. Furthermore, large amounts of 3-O-methyl dopa, the methyl product of L-dopa, are produced in PD patients receiving L-dopa treatment, and L-dopa induces methionine adenosyl transferase, the enzyme that produces SAM. The results show that, at 0.5 hr, L-dopa (100 mg/kg) decreased the methyl donor, S-adenosylmethionine (SAM) by 36%, increased its metabolite S-adenosylhomocysteine (SAH) by 89% and increased methylation (SAH/SAM) by about 200%. All parameters returned to control values within 4 hr. But 2, 3 and 4 consecutive injections of L-dopa, given at 45 min intervals, depleted SAM by 60, 64 and 76% and increased SAM/SAH to 818, 896, and 1524%. L-dopa (50, 100 and 200 mg/kg) dose-dependently depleted SAM from 24.9 +/- 1.7 nmol/g to 13.0 +/- 0.8, 14.7 +/- 0.8 and 7.7 +/- 0.7 nmol/g, and increased SAH from 1.88 +/- 0.14 to 3.43 +/- 0.26, 4.22 +/- 0.32 and 6.21 +/- 0.40 nmol/g. Brain L-dopa was increased to 326, 335 and 779%, dopamine to 138, 116 and 217% and SAH/SAM to 354, 392 and 1101%. The data show that L-dopa depletes SAM, and increases methylation 4-5 times more than dopamine, therefore, methylation may play a role in the actions of L-dopa. This and other studies suggest that the high level of utilization of methyl group by L-dopa leads to the induction of enzymes to replenish SAM and to increase the methylation of L-dopa as well as DA. These changes may be involved in the side effects of L-dopa.     

Effects of Catechol-O-Methyltransferase Inhibitors and L-3,4-Dihydroxyphenylalanine With or Without Carbidopa on Extracellular Dopamine in Rat Striatum

Abstract: The effects of two new catechol- O -methyltransferase (COMT) inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3- O -methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT inhibitors markedly inhibit the O -methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation. A significant effect can be achieved even by inhibiting only the peripheral COMT activity. The data suggest that COMT inhibitors may be of clinical importance as adjuncts in the treatment of Parkinson's disease.     

Production of functional recombinant tyrosine hydroxylase by the BPV-1 expression plasmids in the cell cultures

Bovine papilloma virus type-1 (BPV-1)-based expression plasmids TkBPVTH and CGalBPVTH encoding the rat tyrosine hydroxylase (TH) enzyme have been designed for the development of gene therapy for experimental Parkinson's disease. The aim of the present work was to examine the transfection of BPVTH plasmids to express a dopaminergic transgene in the monkey CV1-P fibroblast, rat C6 glioma and human NHA astrocyte cell cultures. The biological function of the transgene was estimated by analyzing the production of recombinant TH mRNA and protein, and the synthesis of L-dopa and dopamine. The highest transfection efficiency was obtained using TkBPVTH plasmids (5 microg). Furthermore, the expression of TkBPVTH plasmids was associated with significant synthesis of TH enzyme and L-dopa in the C6 and NHA cell cultures.     

老年帕金森病患者康复护理的效果分析

目的探讨老年帕金森病患者康复护理的效果。方法选取我科老年帕金森病患者100例,按随机表法分为观察组和对照组,观察组给予康复护理,对照组给予常规护理,比较两组患者治疗前后日常生活能力及帕金森病症状评分量表(UPDRS)评分情况。结果护理干预后,两组患者的UPDRSⅡ、Ⅲ评分均低于干预前(均P0.05),且观察组显著优于对照组(P0.05)。结论老年帕金森病患者实施康复护理可提高临床疗效,提高患者日常生活能力,增强战胜疾病的信心。     

Age-related changes in saccadic eye movements in healthy subjects and patients with Parkinson's disease

Age-related changes in characteristics of saccadic eye movements (latency, duration and percentage of multistep saccades) in healthy subjects and patients with Parkinson's disease were evaluated. Healthy volunteers were divided into 6 age groups (17-20 years, 21-30 years, 31-40 years, 41-50 years, 51-60 years, 61-75 years), parkinsonian patients into 3 age groups (41-50 years, 51-60 years, 61-75 years). According to our data, saccade characteristics depend upon age in both healthy subjects and parkinsonian patients. In healthy volunteers the percentage of multistep saccades and the mean saccade latency increase significantly after the age of 60. Values of these characteristics in patients with Parkinson's disease significantly exceed the values in the corresponding age groups of healthy subjects. The "disease" factor (MANOVA) has a greater influence on saccade latency and percentage of multistep saccades then the "age" factor. The duration of single saccades depends on age to a smaller extent and does not change in patients with Parkinson's disease. The peculiarities of neurodegenerative processes during normal aging and aging with Parkinson's disease are discussed.     

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease

Summary 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.