Oral Administration Of Levodopa Research Articles

Recent Progress in Gene Therapy for Parkinson’s Disease

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD.

Behavioral improvement in MPTP-treated nonhuman primates in the HALLWAY task after transfer of TH cDNA to host astrocytes.

Parkinson's disease is a neurodegenerative disease, resulting from deterioration of the substantia nigra which in turn leads to a decrease of dopamine levels in the striatum. Clinically the syndrome is characterized by motor alterations that are treated by the oral administration of levodopa. However, this treatment typically loses efficacy over time and therefore new treatments that procure a steady long term supplement of dopamine are needed. Here we tested the expression of a tyrosine hydroxilase (TH) transgene in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated primates own astrocytes. The transgene, whose expression of TH cDNA was controlled by a glial fibrillary acidic protein (GFAP) promoter, was injected into MPTP treated primate's brains using liposomes as a delivery system. Monkeys were tested before and after MPTP administration, and after gene therapy treatment on the HALLWAY behavioral task. Results showed both transgene expression and significant behavioral improvements in the hallway task after the TH cDNA transfer. The behavioral recovery observed in the primates whose astrocytes expressed rat TH, is a first step that warrant further studies using primate's astrocytes as a good cell lineage to express therapeutic molecules.

Translational Neurodegeneration, a platform to share knowledge and experience in translational study of neurodegenerative diseases

Translational Neurodegeneration, a platform to share knowledge and experience in translational study of neurodegenerative diseases

Combination Treatment of Low-Frequency rTMS and Occupational Therapy with Levodopa Administration: An Intensive Neurorehabilitative Approach for Upper Limb Hemiparesis After Stroke

ABSTRACTThe combination treatment of low-frequency repetitive transcranial magnetic stimulation (rTMS) and intensive occupational therapy was applied with concomitant oral administration of levodopa in five post-stroke patients with upper limb hemiparesis (age at treatment: 56–66 years; interval between onset of stroke and treatment: 18–143 months) as a 15-day inpatient protocol. Daily levodopa administration of 100 mg was initiated 1 week before admission and continued until 4 weeks after discharge. Low-frequency rTMS of 1 Hz was applied to the contralesional hemisphere for 40 min daily (two 20-min sessions) combined with intensive occupational therapy consisting of 60-min one-on-one training and 60-min self-exercise. Motor function of the affected upper limb was serially evaluated with the Fugl–Meyer Assessment and the Wolf Motor Function Test. At the end of the treatment, all patients showed improved motor function in the affected upper limbs. In some patients, the improvement was maintained until 4 weeks after discharge. No patient showed any adverse effect from the intervention. Our proposed protocol featuring levodopa administration, low-frequency rTMS, and intensive occupational therapy could provide a safe and feasible intervention for upper limb hemiparesis after stroke.

Continuous rotigotine administration reduces dyskinesia resulting from pulsatile treatment with rotigotine or l-DOPA in MPTP-treated common marmosets

We previously showed that continuous infusion of rotigotine resulted in less dyskinesia than repeated pulsatile rotigotine administration or repeated oral administration of l-DOPA in MPTP-treated marmosets. Now we investigate whether continuous rotigotine delivery modifies established dyskinesia induced by prior exposure to repeated pulsatile administration of l-DOPA or rotigotine in MPTP-treated common marmosets. Repeated oral administration of l-DOPA or subcutaneous bolus administration of rotigotine over 28 days improved motor deficits but resulted in the onset of dyskinesia of moderate intensity. When these animals were switched to a 28-day continuous infusion of rotigotine, the reversal of motor disability was maintained. In those animals initially treated with l-DOPA, there was a small reduction in dyskinesia intensity but a significant reduction in the duration of dyskinesia. However, in animals initially treated with repeated bolus administration of rotigotine, dyskinesia intensity was significantly reduced. Initial treatment with a continuous infusion of rotigotine for 28 days reversed motor disability and resulted in a low incidence of dyskinesia. On switching to repeated oral administration of l-DOPA, the improvement in motor disability was maintained but the propensity of l-DOPA to provoke dyskinesia was not affected. In addition, while the continuous delivery of rotigotine prevented the expression of dyskinesia, the previously demonstrated ability of dopamine agonists to prime for dyskinesia could not be avoided. These data suggest that dyskinesia induced by pulsatile drug treatment may be improved by switching to continuous rotigotine delivery. In addition, while continuous delivery of rotigotine may prime for dyskinesia, it does not lead to its expression.

Pharmacokinetic evaluation and modeling of formulated levodopa intranasal delivery systems

Levodopa ( l-dopa), the metabolic precursor of dopamine, has primarily been used for the treatment of Parkinson's disease (PD) in combination with carbidopa (C-dopa). This study aims to investigate the feasibility of l-dopa nasal delivery systems prepared using maleic acid solution containing 2-hydroxypropyl-β-cyclodextrin, and to develop pharmacokinetic models. Following oral or intravenous administration of l-dopa plus C-dopa and intranasal dosing of l-dopa in the presence and absence of C-dopa to the rat, the concentrations of l-dopa in plasma and brain were determined using HPLC. The pharmacokinetic profiles were analyzed using non-compartmental and compartmental modeling approaches. Simultaneous nonlinear regression was performed to improve the identifiability of model parameters. l-Dopa was rapidly absorbed into blood and brain. The absolute bioavailabilities of oral and nasal preparations containing C-dopa were 17.7 and 45.4%, respectively. C-dopa caused a 1.2-fold decrease in the elimination rate of l-dopa, indicating decreased metabolism. Although the half-life after nasal administration was relatively short (less than 30 min) in both blood and brain regardless of C-dopa addition, the systemic exposure was promising due to rapid absorption. In conclusion, the l-dopa nasal delivery system could be used as a good rescue therapy for PD patients who experience symptom fluctuation with oral l-dopa administration.

Effect of l-dopa on growth hormone, glucose, insulin, and cortisol response in obese subjects.

Plasma growth hormone, glucose, insulin and cortisol response to oral administration of L-dopa and in insulin-tolerance test were investigated in 18 obese subjects. The results were compared with the results obtained in 10 normal subjects. The obese subjects displayed a lack of growth hormone responsiveness to L-dopa and a diminished GH responsiveness to hypoglycemia. There was no significant difference in glucose response to hypoglycemia in normal and obese subjects. Obese subjects showed normal increments of plasma cortisol following induction of hypoglycemia although there was no consistent cortisol response after L-dopa administration. A blood glucose response following L-dopa administration was seen in most of normal subjects while no increment of blood glucose was noticed in obese subjects.

Levodopa enhances synaptic plasticity in the substantia nigra pars reticulata of Parkinson's disease patients

Parkinson's disease, caused by the loss of dopaminergic nigrostriatal projections, is a debilitating neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability. The dopamine precursor levodopa (L-dopa) is the most effective treatment for the amelioration of Parkinson's disease signs and symptoms, but long-term administration can lead to disabling motor fluctuations and L-dopa -induced dyskinesias (LIDs). Studies in rat striatal slices have shown dopamine to be an essential component of activity-dependent synaptic plasticity at the input to the basal ganglia, but dopamine is also released from ventrally projecting dendrites of the substantia nigra pars compacta (SNc) on the substantia nigra pars reticulata (SNr), a major output structure of the basal ganglia. We characterized synaptic plasticity in the SNr using field potentials evoked with a nearby microelectrode (fEPs), in 18 Parkinson's disease patients undergoing implantation of deep brain stimulating (DBS) electrodes in the subthalamic nucleus (STN). High frequency stimulation (HFS--four trains of 2 s at 100 Hz) in the SNr failed to induce a lasting change in test fEPs (1 Hz) amplitudes in patients OFF medication (decayed to baseline by 160 s). Following oral L-dopa administration, HFS induced a potentiation of the fEP amplitudes (+29.3% of baseline at 160 s following a plateau). Our findings suggest that extrastriatal dopamine modulates activity-dependent synaptic plasticity at basal ganglia output neurons. Dopamine medication state clearly impacts fEP amplitude, and the lasting nature of the increase is reminiscent of LTP-like changes, indicating that aberrant synaptic plasticity may play a role in the pathophysiology of Parkinson's disease.

Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal complex I activity, ATP levels or the expression of Bcl-2, pointing to the lack of its disease-modifying role. On the other hand, its administration with high dose of coenzyme Q10 caused the most marked symptomatic improvement in catalepsy score when compared to its administration with low dose of coenzyme Q10, or when compared to either coenzyme Q10 high dose or L-dopa, respectively. Moreover, administration of high dose coenzyme Q10 with L-dopa provided a significant increase in striatal complex I activity, ATP levels and Bcl-2 expression in comparison to group administered coenzyme Q10 low dose with L-dopa, in addition to the significant restoration of striatal dopamine levels and both plasma and striatal Co Q10 levels. Regarding that L-dopa is viewed as a replacement therapy in parkinsonism, it could be concluded that addition of coenzyme Q10 in a high dose in early parkinson's disease could be recommended based on its proved disease-modifying role on several levels of the proposed mechanisms, including improvement of respiratory chain activity and intervention with neuronal apoptosis. A further research to investigate other apoptosis-targeted compounds will open a new era in the treatment of parkinsonism.

Enteral Levodopa/Carbidopa Infusion in Advanced Parkinson Disease

In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. The safety of enteral infusion of levodopa/carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.

Locomotor response to levodopa in fluctuating Parkinson’s disease

The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the day in patients with fluctuating Parkinson's disease (PD). Stride length, walking speed, cadence and gait variability were measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified Parkinson's Disease Rating Scale (UPDRS) gait score (part 29) was also determined by a movement disorders specialist from video recordings. Subjects arrived in the morning in an 'off' state (no PD medication) and walked for a maximum length of 100 m. They then took their usual morning dose of oral levodopa and repeated the walking task at 13 min intervals (on average) over a 90 min period. Changes in stride length over time were fit with a Hill (Emax) function. Latency (time until stride length increased 15% of the difference between baseline and maximum response) and the Hill coefficient (shape of the 'off-on' transition) were determined from the fitted curve. Latency varied from 4.7 to 53.3 min post-administration [23.31 min (SD 14.9)], and was inversely correlated with age at onset of PD (R = -0.83; P = 0.0004). The Hill coefficient (H) ranged from a smooth hyperbolic curve (0.9) to an abrupt 'off-on' transition (16.9), with a mean of 8.1 (SD 4.9). H correlated with disease duration (R = 0.67; P = 0.01) and latency (R = 0.67; P = 0.01), and increased with Hoehn & Yahr stage in the 'off' state (P = 0.02) from 5.7 (SD 3.5) (H&Y III) to 11.9 (SD 4.7) (H&Y IV). Walking speed correlated with changes in mean stride length, whereas cadence and gait variability did not. UPDRS gait score also reflected improving gait in the majority of subjects (8), providing clinical confirmation of the objective measures of the locomotor response to levodopa. Increasing abruptness (H) of the 'off-on' transition with disease duration is consistent with results from finger-tapping studies, and may reflect reduced buffering capacity of pre-synaptic nigrostriatal dopaminergic neurons. Ambulatory monitoring of gait objectively measures the dynamic locomotor response to levodopa, and this information could be used to improve daily management of motor fluctuations.

Gene therapy using AAV

AAV (adeno-associated virus) vectors are considered to be promising gene-delivery vehicles for gene therapy, because they are derived from non-pathogenic virus, efficiently transduce non-dividing cells, and cause long-term gene expression. Appropriate AAV serotypes are utilized depending on the type of target cells. Among various neurological disorders, Parkinson's disease (PD) is one of the most promising candidates of gene therapy. PD is a progressive neurodegenerative disorder that predominantly affects dopaminergic neurons in the substantia nigra. One of the major approaches to gene therapy of PD is the intrastriatal expression of dopamine (DA)-synthesizing enzyme genes. As for the initial step of clinical application, AAV vector-mediated AADC (aromatic L-amino acid decarboxylase; the enzyme converting L-DOPA to DA) gene transfer in combination with oral administration of L-DOPA would be appropriate, since DA production can be regulated by adjusting the dose of L-DOPA. Second, intramuscular injection of AAV vectors is appropriate to protein-supplement gene therapy. Monogenic diseases such as hemophilia and Fabry disease are suitable candidates. Regarding cancer gene therapy, AAV vectors may be utilized to inhibit tumor angiogenesis, metastasis, and invasion. When long-term transgene expression in stem cells is needed, a therapeutic gene should be introduced with a minimal risk of insertional mutagenesis. To this end, site-specific integration into the AAVS1 locus on the chromosome 19 (19q13.4) by using the integration machinery of AAV would be particularly valuable.

Polysomnographic and pharmacokinetic findings in levodopa‐induced augmentation of restless legs syndrome

Augmentation, defined as a loss of circadian recurrence with progressively earlier daily onset and increase in the duration, intensity, and anatomy of symptoms, not compatible with the half-life of the drug, is associated with dopaminergic treatment in restless legs syndrome (RLS) patients. The pathogenesis of augmentation is unclear. We describe a patient with idiopathic RLS who developed augmentation after 8 months of levodopa treatment. Videopolysomnographic and pharmacokinetic studies with monitoring of plasma levodopa levels demonstrated marked motor hyperactivity during augmentation, with anarchic discharges of motor unit potentials, tonic grouped discharges and flexor spasms, associated with painful dysesthesia. Symptoms and signs of augmentation were related to low plasma levodopa levels, abating 75 minutes after oral levodopa administration and reappearing after 3 hours, closely mirroring the rapid rise and fall of plasma levodopa concentration. This case is the first report in which RLS augmentation is shown to be characterized by motor hyperkinesias paralleling levodopa plasma pharmacokinetic profile.

Attenuation of fluctuating striatal synaptic dopamine levels in patients with Parkinson disease in response to subthalamic nucleus stimulation: a positron emission tomography study

The "wearing-off" phenomenon often hampers the treatment of Parkinson disease (PD). Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to ameliorate the wearing-off phenomenon, the mechanism by which it does this remains unclear. As part of an inquiry into the mechanism of STN DBS, the authors measured synaptic dopamine levels in the striatum by performing positron emission tomography (PET) with [11C]raclopride. Three patients with PD who were experiencing the wearing-off phenomenon underwent PET scanning before and after DBS of the STN. The clinical features in these patients were evaluated by applying the Hoehn and Yahr, United Parkinson's Disease Rating, and Schwab and England Activities of Daily Living Scales. Before and after surgery, PET scans were obtained using [11C]raclopride prior to and 1 hour following an oral administration of levodopa. Regions of interest for the [11C]raclopride binding potential (RacloBP) were set in the bilateral putamen and the caudate nucleus. All clinical scores were dramatically improved postoperatively. Deep brain stimulation of the STN reduced the baseline RacloBP in both the putamen and caudate nucleus, but the differences between the pre- and postoperative levels were insignificant. Before DBS of the STN, the levodopa administration significantly reduced RacloBP in the putamen (p < 0.0001). Postoperatively the drug-induced reduction in RacloBP became statistically insignificant. The drug-induced increase in synaptic dopamine concentrations in the putamen preoperatively was estimated to be approximately four times higher than that after surgery (p < 0.01). The drug-induced RacloBP change in the caudate nucleus was similar to that in the putamen, although the magnitude of the change was lower (p < 0.005). The drug-induced increase in the caudate nucleus was also reduced postoperatively (p < 0.05). Deep brain stimulation of the STN induces the stabilization of synaptic dopamine concentrations in the striatum and may attribute to the alleviation of levodopa-related motor fluctuations.

Coordinated and Spatial Upregulation of Arc in Striatonigral Neurons Correlates With L-Dopa-Induced Behavioral Sensitization in Dyskinetic Rats

Although oral administration of L-Dopa remains the best therapy for Parkinson disease, its long-term administration causes the appearance of abnormal involuntary movements such as dyskinesia. Although persistent striatal induction of some genes has already been associated with such pathologic profiles in hemiparkinsonian rats, molecular and cellular mechanisms underlying such long-term adaptations remain to be elucidated. In this study, using a rat model of L-Dopa-induced dyskinesia, we report that activity regulated cytoskeletal (Arc)-associated protein is strongly upregulated in the lesioned striatum and that the extent of its induction further varies according to the occurrence or absence of locomotor sensitization. Moreover, Arc is preferentially induced, along with FosB, nur77, and homer-1a, in striatonigral neurons, which express mRNA encoding the precursor of dynorphin. Given the likely importance of Arc in the regulation of cytoskeleton during synaptic plasticity, its upregulation supports the hypothesis that a relationship exists between cytoskeletal modifications and the longlasting action of chronically administrated L-Dopa.

Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias.

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.

Detection of levodopa, dopamine and its metabolites in rat striatum dialysates following peripheral administration of l-DOPA prodrugs by mean of HPLC–EC

A high performance liquid chromatography (HPLC) method was developed to detected simultaneously l-dihydroxyphenylalanine ( l-DOPA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum dilaysates following oral administration of l-DOPA or its prodrugs. The chromatographic system uses a reversed-phase C 18 column with electrochemical detection at +0.30 V. Mobile phase consisted of 0.05 M citric acid, sodium EDTA 50 μM, sodium octylsulphonate 0.4 nM at pH of 2.9 and 8% methanol (v/v) at a flow rate of 1 ml/min. The calibration curves were linear over the concentration range of 10 nm to 100 μM and the lower limits of detections were 125 fmol for l-DOPA, 50 fmol for DOPAC, 250 fmol for DA and 150 fmol for HVA at signal noise to ratio of 3. The repeatability (or intra-day precision), expressed by the relative standard deviation, were better than 4%. The construction of microdialysis probes has been described. The in vitro relative recoveries of each microdialysis probe were evaluated and the results show that they are similar and reproducible for all the analytes with CVs from 1 to 4%. The HPLC–EC method was applied to detect the extracellular levels of l-DOPA, DA, DOPAC and HVA in the striatum dialysates of freely moving rats after oral administration of six new potential l-DOPA prodrugs.

Psychomotor, neuroendocrine and behavioural effects after oral administration of levodopa in normal volunteers

The oral administration of a single dose of levodopa ( l-dopa) in 10 healthy human male subjects induced cognitive, not motor, changes during figure-copying tasks that were unrelated to the neuroendocrine and behavioural effects of levodopa. Results point to a decrease in alertness induced by levodopa.

An intermittent, controlled-rate, slow progressive degeneration model of Parkinson’s disease: antiparkinson effects of Sinemet and protective effects of methylphenidate

The causes of nigrostriatal neuron degeneration in Parkinson’s disease (PD) are not known, but it has been suggested that exogenous or endogenous factors or neurotoxins may play a role. The degree of vulnerability to neurotoxins or other potential mediators of nigral dopamine cell death is thought to be important in understanding Parkinson’s disease. In most animal models, the rate of terminal degeneration and corresponding functional impairment is too rapid to investigate effectively either cell vulnerability or the potential benefits of some neuroprotective treatments. In the present study, a new model of Parkinson’s disease is described that might help in addressing the issue of nigral cell vulnerability and to evaluate interventions with clinical potential. 6-Hydroxydopamine (6-OHDA) was infused in escalating, intrastriatal doses over several weeks. Control animals received multiple infusions of vehicle at the same volume. Behavioral testing was carried out between each infusion, including forelimb-use and somatosensory function. A symptomatic threshold was established for each animal, indicating the amount of neurotoxin required to induce a stable deficit. Oral administration of l-DOPA (Sinemet) ameliorated limb-use asymmetries acutely. An immunocytochemical assay for tyrosine hydroxylase, a dopamine cell marker, revealed a partial loss of immunoreactive cells in the substantia nigra. Animals that were co-administered methylphenidate (MPH), a dopamine transport inhibitor, along with the 6-OHDA were spared from the behavioral and neurochemical effects of 6-OHDA, despite receiving more than twice as much neurotoxin as controls. These data suggest that establishing a symptomatic threshold preclinically may help researchers evaluate potential treatments and model individual and group resistance to nigrostriatal insults.

Circadian Variation in Neuroendocrine Response to L-dopa in Patients with Restless Legs Syndrome

To investigate circadian changes in dopaminergic function by means of a neuroendocrine challenge (growth hormone and prolactin responses to an acute oral administration of L-dopa) in patients with idiopathic restless legs syndrome (RLS) and controls. Randomized administration of the L-dopa neuroendocrine challenge. Sleep disorders laboratory at a 500-bed academic hospital. Twelve patients diagnosed with idiopathic RLS and 12 age- and sex-matched healthy controls. Following a comprehensive evaluation that included nocturnal polysomnographic study, all participants underwent the L-dopa neuroendocrine challenge on 2 occasions (11 am and 11 pm). Subjects were previously randomly assigned to the time of first challenge (11 am or 11 pm). On each occasion, subjects took 200 mg of L-dopa (plus 50 mg carbidopa) by mouth. Blood was drawn 20 minutes and 5 minutes before administration of the drug, as well as 15, 30, 45, 60, 75, 90, 102, and 120 minutes after administration. Prechallenge levels of plasma values of growth hormone or prolactin did not differ in the 2 subject groups. Following only the nighttime administration of L-dopa, RLS patients manifested a more pronounced inhibition of prolactin release and an increase in growth hormone secretion. Prolactin plasma levels were significantly correlated to the periodic limb movement index on the polysomnogram. These findings may reflect enhanced circadian variations in dopaminergic function and support an increased sensitivity at night of dopamine receptors in patients with RLS.