Rationale for dopamine agonist use as monotherapy in Parkinson's disease

Dopamine agonists are increasingly being used in the initial treatment of patients with de-novo Parkinson's disease because they provide symptom relief and a low risk of the dyskinesia frequently associated with levodopa. Evidence is also mounting in preclinical models that dopamine agonists protect dopaminergic neurons from the toxic effects of oxidative stress and the by-products of dopamine and L-dopa metabolism. Ergot derivatives, such as pergolide, induce minor side-effects and provide significant and sustained improvements in motor function in patients with early Parkinson's disease. Dopamine agonists also appear to reduce the loss of functional dopamine transporters when used early in the disease course, and these factors combine to build a case for the use of dopamine agonists in early-stage Parkinson's disease.     

Dopamine dysregulation syndrome in Parkinson's disease

PURPOSE OF REVIEW: Dopamine replacement therapy in Parkinson's disease ameliorates motor symptoms. However, it has recently been recognized that a small sub-group of patients suffer motor and behavioural disturbances attributable to taking quantities of medication well beyond the dose required to treat their motor disabilities. This review examines the phenomenology of dopamine dysregulation syndrome in relation to the current understanding of basal ganglia function and its impact on long-term management. RECENT FINDINGS: Cortico-striato-thalamic circuits are implicated in the behavioural and motor disturbances associated with compulsive medication use in Parkinson's disease. Advances in understanding of the role of dopamine in psychostimulant addiction are important in helping to understand dopamine dysregulation. SUMMARY: Recognition of dopamine dysregulation syndrome and characterization of its phenomenology supports the notion that the medication used to treat Parkinson's disease can disrupt basal ganglia mediated motor and behavioural functioning. Refinement of clinical strategies to predict, identify and manage this syndrome will aid the future treatment of motor and non-motor complications of Parkinson's disease.     

Dopamine agonists in the treatment of Parkinson's disease

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.     

Comparing dopamine agonists in Parkinson's disease

Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.     

Treatment of Parkinson''s disease

The aim of current treatment of Parkinson's disease is to ameliorate the symptoms while seeking to lessen the potential development of late levodopa complications. To this end, there is ample evidence that the early use of dopamine agonists is beneficial in younger Parkinsonian patients but monotherapy with dopamine agonists is for only a select few. Nonergot dopamine agonists offer the potential for fewer side effects. Lower dose levodopa therapy delays the onset and reduces severity of dyskinesia and end of dose failure. However levodopa remains the treatment of choice in Parkinson's disease and should not be restricted unnecessarily in patients with disability. There is no evidence that levodopa is toxic to dopaminergic neurons in people with Parkinson's disease. As yet, no drugs are of proven neuroprotective value. Dopamine agonists, catechol-o-methyltransferase inhibitors, amantadine and apomorphine have differing but beneficial roles in the management of levodopa side effects. Ablative surgery and deep brain stimulation of thalamus, globus pallidus and subthalamic nucleus are increasingly available but choice of procedure depends not just on patient symptomatology, but also on local experience and results. Ideally, deep brain stimulation is the treatment of choice as it offers less morbidity than bilateral ablative surgery, the possibility of postoperative adjustments and the potential for reversibility if better treatments become available.     

Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease

Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.     

The putative neuroprotective role of dopamine agonists in parkinson’s disease

Parkinson's disease is probably caused by a combination of genetic and environmental factors, which trigger a cascade of events that lead to the cell death of the dopamine-containing neurons of the substantia nigra pars compacta. These processes include oxidative stress, mitochondrial dysfunction, excitotoxicity with excess of nitric oxide formation, glial and inflammatory abnormalities and apoptosis. Dopamine agonists are chemical compounds that act directly on the dopamine receptors without any previous enzymatic biotransformation. Besides their symptomatic antiparkinsonian effect, these drugs may have neuroprotective properties in Parkinson's disease through different possible mechanisms: (a) stimulation of dopamine auoreceptors, reducing thereby dopamine turnover; (b) direct antioxidant effects; (c) reduction of excitotoxicity induced by excessive subthalamic nucleus firing; (d) inhibition of mitochondrial permeability; (e) induction of trophic factors. Dopamine agonists have already shown neuroprotective effects on dopaminergic cells against a variety of neurotoxins in several in vitro and in vivo studies. Clinical studies to detect changes in the progression of the underlying neurodegenerative process in patients with Parkinson's disease treated with dopamine agonists, by assessing the dopamine terminal function in the striatum by means of PET and SPECT techniques are under way.     

How to succeed in using dopamine agonists in Parkinson's disease

Dopamine receptor agonists are assuming increased importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, tolerability of these drugs can be a problem. Identifying patients who are at increased risk of adverse effects is central to using dopamine agonists in PD. The newer agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side-effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy.     

Arguments for the use of dopamine receptor agonists in clinical and preclinical Parkinson's disease

On the basis of experimental studies which have demonstrated deleterious effects of L-DOPA (L-3,4-dihydroxyphenylalanine) in vivo and in vitro, it has been suggested that L-DOPA itself may contribute to the progression of Parkinson's disease. This hypothesis is, for many clinicians, the rationale for postponing the employment of and reducing the applied dosage of L-DOPA and for beginning therapy with dopamine receptor agonists or the monoamine oxidase type B (MAO-B) inhibitor selegiline. Furthermore, clinical studies have demonstrated that early treatment with dopamine receptor agonists is associated with a lower incidence of motor fluctuations and dyskinesia. Dopamine receptor agonists exert their symptomatic effect by directly activating dopamine receptors, bypassing the presynaptic synthesis of dopamine and the degenerating nigro-striatal dopaminergic system. They can thus also be of benefit late in the therapy of the disorder. In addition, the pharmacological profile of dopamine receptor agonists suggests a possible neuroprotective effect. This paper reviews briefly the pharmacology of dopamine receptor agonists and basic knowledge concerning the dopamine receptor stimulation which underlies their therapeutic effect. Preclinical approaches for demonstrating neuroprotective effects and their clinical relevance are also discussed.     

Steroids‐Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Introduction: Dopamine cell loss is well documented in Parkinson's disease and dopamine hypofunction is proposed in certain depressive states. At the opposite, dopamine hyperactivity is an enduring theory in schizophrenia with extensive supporting evidence. Aims: This article reviews the sex differences in these diseases that are the object of many studies and meta‐analyses and could be explained by genetic differences but also an effect of steroids in the brain. This article then focuses on the extensive literature reporting on the effect of estrogens in these diseases and effects of the other ovarian hormone progesterone as well as androgens that are less documented. Moreover, dehydroepiandrosterone, the precursor of estrogens and androgens, shows effects on brain dopamine neurotransmission that are reviewed. To investigate the mechanisms implicated in the human findings, animal studies are reviewed showing effects of estrogens, progesterone, and androgens on various markers of dopamine neurotransmission under intact as well as lesioned conditions. Discussion: For possible future avenues for hormonal treatments in these central nervous system diseases, we discuss the effects of selective estrogen receptor modulators (SERMs), the various estrogen receptors and their specific drugs as well as progesterone drugs. Conclusion: Clinical and experimental evidence supports a role of steroid–dopamine interactions in the pathophysiology of schizophrenia, depression and Parkinson's disease. Specific steroidal receptor agonists and SERMs are available for endocrine and cancer treatments and could find other applications as adjunct treatments in central nervous system diseases.     

Dopamine agonists in Parkinson's disease

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.     

The dopamine receptor agonist lisuride attenuates iron-mediated dopaminergic neurodegeneration

Many dopamine agonists used in the treatment of Parkinson's disease are suggested to be potentially neuroprotective. On the basis of its structure, the dopamine agonist lisuride may share this characteristic. In the current study discrete asymptomatic lesions were produced by the injection of iron-laden neuromelanin into the rat substantia nigra and the animals treated with lisuride to determine the protective potential of this substance. Two treatment regimes were utilised. In the neuroprotective protocol, animals were treated with 0.1 mg.kg(-1) lisuride twice daily 3 days prior to, and 7 days following, the iron lesion. In the neurorescue protocol, the animals received 0.1 mg.kg(-1) lisuride twice daily for 1 week beginning on the fourth day post surgery. Eight weeks post surgery, tyrosine hydroxylase-positive neurons surrounding the injection site (33% of total nigral volume) were counted. Dopamine neuron number in iron-lesioned animals was reduced to 50% of that in vehicle-injected animals. The absence of motoric disturbances or a striatal dopamine deficit in these animals suggests a subclinical dopaminergic lesion. Dopamine neuron number in the quantified area in sham-injected animals receiving lisuride or iron-lesioned animals receiving lisuride in both the neuroprotection and neurorescue groups were not significantly reduced. These results suggest that lisuride can protect neurons against iron-induced cell death and might thus be neuroprotective in Parkinson's disease.     

Dopamine agonists and neuroprotection in Parkinson's disease

Dopamine agonists are effective in reversing the motor symptoms of Parkinson's disease (PD). They have also shown that they can delay or prevent the onset of motor complications associated with levodopa use. Recent attention has focused on the possible role for dopamine agonists in neuroprotection. Numerous studies have demonstrated that a variety of dopamine agonists can protect dopaminergic neuronal function in several toxin model systems. Pramipexole in particular has shown efficacy in reducing toxicity to MPTP, MPP, rotenone and 6-hydroxydopamine. Recent studies in early PD using imaging parameters as a surrogate marker of dopaminergic neuronal integrity have shown that pramipexole and ropinirole can apparently retard the rate of cell loss. These observations are of considerable interest, but additional studies are required to confirm a neuroprotective function for these dopamine agonists.     

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.     

Distribution and function of dopamine D1, D2 receptor]

Positron emission tomography (PET) techniques have made it possible to measure changes in target molecular in living human brain. PET can be used to investigate various brain functions such as receptors, transporters, enzymes and various biochemical pathways; therefore, it could be a powerful tool for molecular imaging of functional neurotransmission. Since dopamine is an important molecule for pathophysiology of Parkinson's disease and schizophrenia, we reviewed in vivo imaging studies focusing on dopaminergic transmission. Dopamine D2 receptor occupancy by antipsychotics and it's time-course have been measured using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish the rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery. On the other hand Dopamine D1 receptor is highly expressed in the prefrontal cortex, has been implicated in the control of working memory, seeking, craving, reward. We propose that dysfunction of Dopamine D1 receptor signalling in the prefrontal cortex may contribute to the negative symptoms and cognitive deficits seen in schizophrenia and we suggest that Dopamine D1 receptor binding and cerebral blood flow changes in ventral striatum play the important role of cigarette craving.     

ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia

Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine beta-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.     

Dopamine: a key regulator to adapt action, emotion, motivation and cognition

Dopamine is expressed in restricted brain areas involved in numerous integrative functions contributing to automated behaviours that are highly adaptive. During ontogenesis, dopamine can have a trophic action, which influences cortical specification directly, especially in prefrontal areas. Such a role is attested by the close relationships existing between the development of dopamine cortical innervation and cognitive abilities. Interestingly, such a proposal is reinforced by phylogenetic data. During the last stages of evolution in mammals, the characteristic extension of dopamine cortical innervation is also correlated with the development of cognitive capacities. More generally, the contribution of dopamine will be to increase the processing of cortical information through basal ganglia, either during the course of evolution or development. In this respect, dysmaturation suspected in schizophrenia and attention deficit-hyperactivity disorder in children can emphasize such a defect in basal ganglia processing. Remarkably, these diseases are improved by dopamine antagonists and agonists, respectively. In this line of evidence, experimental studies showed that selective lesions of the dopamine neurones in rats or primates can actually provide motor, limbic and cognitive deficits, in later cases especially when the mesocorticolimbic dopamine pathways are altered. Data resulting from lesion studies also showed significant alteration in attentional processes, thus raising the question of the direct involvement of dopamine in regulating attention. Dopamine can act as a powerful regulator and integrator of different aspects of brain functions. For example, in Parkinson's disease, besides motor impairment, dopamine degeneration is also expressed by alterations of both limbic, executive and cognitive functions, both improved by dopamine receptor agonists and dopa therapy. Dopamine has thus to be considered as a key regulator that contributes to behavioural adaptation and to the anticipatory processes necessary for preparing voluntary action consequent upon intention. In this respect, the alteration of dopamine transmission with age could contribute to cognitive impairment. Therefore, to normalize dopamine transmission pharmacologically could actually improve the cognitive and limbic deficits during normal aging, as it does in psychiatric and neurological disorders.     

Dopamine agonists

Dopamine agonists provide an effective means of treating early, middle, and late stages of Parkinson's disease. This article outlines the advantages and disadvantages of dopamine agonists as compared with levodopa therapy. The features and costs of the four Food and Drug Administration-approved agonists (bromocriptine, pergolide, pramipexole, and ropinirole) and apomorphine, another agonist presently under investigation, are discussed.     

Dopamine D2 and D3 receptor agonists limit oligodendrocyte injury caused by glutamate oxidative stress and oxygen/glucose deprivation

Dopamine receptor activation is thought to contribute adversely to several neuropathological disorders, including Parkinson's disease and schizophrenia. In addition, dopamine may have a neuroprotective role: dopamine receptor agonists are reported to protect nerve cells by virtue of their antioxidant properties as well as by receptor-mediated mechanisms. White matter injury can also be a significant factor in neurological disorders. Using real-time RT-PCR, we show that differentiated rat cortical oligodendrocytes express dopamine D2 receptor and D3 receptor mRNA. Oligodendrocytes were vulnerable to oxidative glutamate toxicity and to oxygen/glucose deprivation injury. Agonists for dopamine D2 and D3 receptors provided significant protection of oligodendrocytes against these two forms of injury, and the protective effect was diminished by D2 and D3 antagonists. Levels of oligodendrocyte D2 receptor and D3 receptor protein, as measured by Western blotting, appeared to increase following combined oxygen and glucose deprivation. Our results suggest that dopamine D2 and D3 receptor activation may play an important role in oligodendrocyte protection against oxidative glutamate toxicity and oxygen-glucose deprivation injury.     

Workshop III: late motor complications of Parkinson's disease

The aim in the current treatment of Parkinson's disease is to delay L-Dopa administration and to keep the L-Dopa dosage as low as possible. Such a treatment strategy can delay the onset of late motor complications and reduce their severity. L-Dopa remains the most potent anti-parkinsonian medication, but its use for the initial therapy of Parkinson's disease is limited to elderly patients. In all other cases, dopamine agonists, budipine, amantadine and selegiline are primarily used. With the occurrence of late motor complications continuous dopamine receptor stimulation becomes essential. In this situation, combination therapy has to be individualized, with dopamine agonists playing a key role. In addition, COMT inhibitors, budipine, amantadine and selegiline may be used. Anticholinergic drugs are of very limited importance in the current treatment of Parkinson's disease.