D1 and functionally selective dopamine agonists as neuroprotective agents in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that results in major motor disturbances due primarily to loss of midbrain dopamine neurons. The mainstream treatment has been dopaminergic replacement therapy aimed at symptomatic relief, with the gold standard drug being the dopamine precursor levodopa. The general dogma has been that levodopa works primarily by indirectly activating the D(2) family of dopamine receptors. Recently, a number of direct dopamine agonists that target the D(2) and D(3) dopamine receptors have been used as dopaminergic replacement strategies. Although these direct D(2) and D(3) drugs cause only modest improvement in motor function compared to levodopa, they can delay the initiation of levodopa and can act synergistically with levodopa. In addition, they can delay the onset of levodopa-related motor complications. Recent imaging data also suggest that they may have neuroprotective effects. Whereas D(2)/D(3) agonists have received much attention as several drugs are available for clinical trials and usage, there has been a large body of data showing that the D(1) receptor actually may play a larger role in restoration of normal motor function. This review examines the current use of dopamine D(2)/D(3) agonists in treatment of PD and their potential for providing neuroprotection. Furthermore, we also examine the potential that D(1) agonists might have in neuroprotective actions in the disease progression.     

Dopamine agonists in the treatment of non-motor symptoms of Parkinson's disease: depression

Background:  Psychiatric symptoms such as depression are common non-motor comorbidities of Parkinson's disease (PD). Depressive symptoms in patients with PD are a major complication that impairs quality of life independent of motor symptoms. The relationship between PD and comorbid depression is not completely understood.
Methods and Results:  Evidence suggests that both PD and depression may be mediated by degeneration of the dopaminergic system. Recent and ongoing research is exploring the potential role of dopamine agonists in the treatment of depressive symptoms in patients with PD.
Conclusion:  Experimental studies suggest a primary relationship and the importance of dopaminergic mechanisms in PD and depression. Patients with PD and depression might benefit from a global approach. Thus, treatment with dopamine agonists promises to reduce motor complications as well as depressive symptoms, avoiding multiple drug interactions as well as possible antidepressant medication side effects.     

Initial treatment of early Parkinson’s disease: A review of recent, randomized controlled trials

Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson’s disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.     

Subcutaneous continuous apomorphine infusion in fluctuating patients with Parkinson's disease: long-term results

Fluctuations in motor disability and dyskinesias are the major problem in the long-term treatment of Parkinson's disease (PD). Many authors and ourselves have shown that by giving patients a continuous infusion of levodopa it is possible to control motor fluctuations. Levodopa can be administered continuously only be intravenous, intragastric or intrajejunal delivery. Continuous dopaminergic stimulation an be achieved more easily by infusing dopamine agonists subcutaneously. Apomorphine is a potent water-soluble dopamine receptor agonist that has been shown to successfully control motor fluctuation when subcutaneously infused in complicated parkinsonian patients. We report the clinical data of 30 PD patients having at least five years of treatment with subcutaneous continuous apomorphine infusion.     

Neurotransmission in Parkinson’s disease: beyond dopamine

Parkinson’s disease (PD) is most frequently associated with characteristic motor symptoms that are known to arise with degeneration of dopaminergic neurons. However, patients with this disease also experience a multitude of non‐motor symptoms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some of which can be at least as debilitating as the movement disorders and have a major impact on patients’ quality of life. Many of these non‐motor symptoms may be evident prior to the onset of motor dysfunction. The neuropathology of PD has shown that complex, interconnected neuronal systems, regulated by a number of different neurotransmitters in addition to dopamine, are involved in the aetiology of motor and non‐motor symptoms. This review focuses on the non‐dopaminergic neurotransmission systems associated with PD with particular reference to the effect that their modulation and interaction with dopamine has on the non‐motor symptoms of the disease. PD treatments that focus on the dopaminergic system alone are unable to alleviate both motor and non‐motor symptoms, particularly those that develop at early stages of the disease. The development of agents that interact with several of the affected neurotransmission systems could prove invaluable for the treatment of this disease.     

Dopamine agonists: the treatment for Parkinson's disease in the XXI century?

Levodopa combined with a peripheral dopa-decarboxylase inhibitor (DCI) has been considered the therapy of choice for Parkinson's disease (PD). Levodopa is nearly always effective, but has a high incidence of adverse effects with long term use, including response fluctuations (on/off phenomena) and dyskinesias. Dopaminergic agonists, acting directly at the receptor level, would be able to decrease the incidence of these motor complications.In progressive neurodegenerative diseases, such as PD, modification of the rate of disease progression (often referred to as neuroprotection) is currently a highly debated topic. Increased oxidative stress is thought to be involved in nigral cell death, that is characteristic of PD. This oxidative stress may be further exacerbated by levodopa therapy. These mechanisms have been proven in vitro and animal models, but it's relevance in humans remains speculative.Based on the considerations above, the emerging therapeutic strategies for PD advocate early use of dopamine agonists in the treatment of PD. A number of recent well-controlled studies have proven the efficacy of dopamine agonists used as monotherapy. Moreover, as predicted by animal studies, on the long term, dopaminergic agonists induce significantly less motor complications than levodopa.In the last 2years, three new dopamine agonists have been launched, including ropinirole, pramipexole and cabergoline. These new agonists have been added, as therapeutical options to well-established drugs, like pergolide, bromocriptine or talipexole. The recently launched compounds have proven efficacy in monotherapy and as adjunctive therapy to levodopa. Unfortunately, only a very limited amount of comparative data among the different agonists is available. Pergolide has proven to be a superior drug to bromocriptine as adjunctive therapy to levodopa in a significant number of studies and is considered the gold standard dopamine agonist. Nevertheless, none of the recently launched compounds has compared itself against pergolide.A comparison of monotherapy trials is difficult, because of differences in design and populations. In a recently completed trial pergolide was statistically significantly better than placebo in all the efficacy parameters tested, with 57% of pergolide treated patients improving over 30% in the motor section of the UPDRS, as compared to 17% in the placebo arm. Interestingly, these results were obtained in the absence of any other antiparkinsonian drug during the trial. Recent monotherapy trials done with ropinirole and pramipexole achieved also significant improvements as monotherapy, but in these cases selegeline, a drug that causes a symptomatic improvement in PD, was allowed as co-medications during the trial. Not all trials used the same efficacy measures, i.e. monotherapy trials with pergolide and ropinirole used a "responder" based analysis (responder were all patients that improved 30% or more on the motor section of UPDRS), as well as a baseline to endpoint improvement in motor scores. Pramipexole monotherapy trials used only the latter approach, which is clinically less powerful than a responder analysis.Even with the difficulties mentioned above, all the recent trials with dopamine agonists have proven that these drugs are a useful symptomatic long term treatment for PD with or without levodopa and that the early use of dopamine agonists reduces the incidence of motor complications as compared to levodopa.     

GDNF family ligands: a potential future for Parkinson's disease therapy

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor dysfunction that occurs secondary to loss of dopaminergic neurons in the nigrostriatal pathway. Current pharmacotherapies focus on the replacement of lost dopamine to alleviate disease symptoms. However, over time this method of therapy loses effectiveness due to the continued death of dopaminergic neurons. Alternative strategies for the treatment of PD are aimed at modifying the disease state through the preservation of remaining dopamine neurons or even the regeneration of dopamine innervation through the use of neurotrophic factors. Neurotrophic factors are specialized proteins that can promote neuronal development, maintain neuronal health and modulate neuronal function in the ventral midbrain, making them candidates for the treatment of PD. Preclinial studies indicate that members of the glial cell line-derived neurotrophic factor family of ligands are capable of preserving the degenerating dopamine neurons. These promising results moved neurotrophic factor therapy to clinical trials in PD patients. To date, neurotrophic factor therapy is proven to be safe and well-tolerated in humans, but conclusive evidence of efficacy in the clinic remains to be determined. This review will discuss the preclinical and clinical experiments of glial cell line-derived neurotrophic factor family ligands for the treatment of PD.     

Neuropsychological and perceptual defects in Parkinson's disease

Neuropsychiatric, perceptual and cognitive deficits are increasingly recognized as non-motor manifestations of Parkinson's Disease (PD).The premorbid personality profile of PD patients is characterized by a number of traits which figure prominently after the disease becomes manifest. In particular, less novelty seeking is one premorbid trait providing an understanding of later cognitive deficits. Anxiety and depression have been shown to precede in some patients motor manifestations and cannot be attributed to anti-parkinsonian therapy. Some neuropsychiatric manifestations and in particular hallucinosis are linked to select perceptual and cognitive changes. Cognitive deficits are common in PD, in particular in younger onset patients. Current animal studies link genetic differences in the dopamine transporter and dopamine catabolic enzyme system to select cognitive impairments attributed to frontal lobe dysfunction.Visuo-cognitive impairment is prevalent in PD. Retinal dopaminergic deficiency has been shown in patients and in the animal model of PD. Visuo-spatial deficits, however, are not simply passive reflections of retinal deficiency. In addition to vision, saccadic eye movements are affected in PD whether they contribute to visuo-spatial dysfunction is unknown. However, recent functional Magnetic Resonance Imaging (fMRI) and electroencephalogram (EEG) studies show an essential role of the occipital cortex in saccadic eye movements and positron emission tomography (PET) studies show occipital hypometabolism in PD. Visual and eye movement studies suggest that certain neuropsychiatric and cognitive deficits in PD are linked to the visual system. Synchrony of signals are essential for the co-operation of distributed neuronal network engaged in sensory-motor coordination. Local, dopaminergic neuronal groups in the retina, basal ganglia and frontal cortical memory system are affected in PD. These connections may not primarily rely on dopamine as a neurotransmitter. It is suggested that to understand visuocognitive changes we should consider pathology affecting neuronal connections, necessary for binding parallel distributed networks.     

Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease

Patients receiving oral levodopa, the standard treatment for Parkinson's disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety.     

Pharmacokinetic and pharmacodynamic considerations in management of motor response fluctuations in Parkinson's disease

Recent advances in the understanding of the pharmacokinetics of levodopa and other anti-Parkinson agents have brought about the development of rational approaches to the management of levodopa-related fluctuations in motor performance that plague the majority of patients with advanced PD. The rapid systemic clearance of levodopa underlies the "short duration" response to the drug, which is progressively unmasked as PD progresses and central dopamine synthetic and storage capacity can no longer buffer fluctuations in plasma levodopa levels. Dyskinesias may be considered a secondary pharmacodynamic consequence of such pharmacokinetically induced oscillations in brain dopamine levels. Therapeutic approaches aimed at stabilizing brain dopaminergic activity include the use of slowly releasing galenic formulations of levodopa, synthetic dopamine agonists of long-lasting biologic activity, and drugs such as deprenyl that act as "dopamine extenders." It remains to be seen whether early use of such treatment approaches will reduce the prevalence of motor response fluctuations, which are one of the most disabling complications of long-term treatment of PD.     

Treatment of Parkinson's disease: levodopa as the first choice

The introduction of levodopa in the 1960s revolutionised the treatment of Parkinson's disease (PD), and it continues to be the most effective symptomatic therapy. The vast majority of PD patients who start treatment with L-dopa experience good to excellent functional benefit. In vitro studies with high doses of L-dopa and absent glia had shown that it may be neurotoxic, but other tissue culture studies show L-dopa to be neuroprotective. Most studies in animal models and clinico-pathological and mortality studies in humans failed to show evidence in favour of accelerated dopaminergic neuronal loss with long-term L-dopa therapy.L-dopa continues to be beneficial throughout the course of PD, although as the disease progresses, escape of some symptoms from adequate control may occur and refractory disabilities such as impaired balance, dysarthria, cognitive decline and hallucinations may emerge. Treatment of advanced PD may also be complicated by the emergence of motor fluctuations and dyskinesias. Studies in animal models and in humans show that these motor complications are not specific to a particular dopaminergic agent, but that they are related both to the extent of the striatal lesion and to the mode of application of dopaminergic agents: Pulsatile administration of L-dopa and of the dopamine agonist apomorphine causes more motor complications than continuous striatal dopaminergic receptor stimulation, and continuous administration can alleviate existing dyskinesias and fluctuations. Several controlled studies comparing levodopa and dopamine agonists as initial treatment have attempted to answer the question whether delaying L-dopa therapy can reduce the occurrence of motor complications. Three medium-term (3-5 years) and one 10-year study showed less dyskinesia in the first five years of treatment in patients who had started therapy with a dopamine agonist. However, these studies also consistently showed that levodopa provided better functional improvement in the first years of treatment. Ten-year follow-up data in patients randomised to L-dopa or bromocriptine also showed a slightly lower incidence of motor complications in the bromocriptine arm. However, this difference was not significant for the clinically relevant moderate and severe forms of dyskinesias and fluctuations, and was achieved at the expense of significantly worse disability scores during the first years of therapy. Furthermore, the relative impact of motor disability and dyskinesias on patients' quality of life remains to be established. Concordance is essential in the optimum treatment of PD and patients should be informed of the various therapeutic options available. Treatment should respect individual patients' needs and take into account their particular functional disabilities and specific handicaps. Low-dose L-dopa therapy (up to 400 mg/day), however, remains the most effective initial treatment of choice for the majority of patients.     

Apomorphine effects on the hippocampus

Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson's disease(PD). The dopaminergic agonists like apomorphine are related to oxidative processes that could induce cell damage and the functional impairment of some structures in the brain. However, most information about apomorphine in literature is focused on the improvement of the motor problems characteristic of PD, but little is known about the effects on cognitive behaviors and brain structures indirectly related to motor function. The presence of dopaminergic receptors in the hippocampus has recently been discovered, in connection with cognitive behaviors like learning and memory, these receptors are needed in neuronal plasticity. There has been a growing interest to know if this structure could be compromised by the effect of apomorphine and elucidate if part of the cognitive impairment present in the PD is due to the effect of apomorphine. In this mini-review, we summarized how apomorphine has been used since its creation, we discuss the latest information about its effect on the hippocampus and also the future perspectives to fully understand the effects of this compound.     

Continuous drug delivery in early- and late-stage Parkinson’s disease as a strategy for avoiding dyskinesia induction and expression

The treatment of the motor symptoms of Parkinson’s disease (PD) is dependent on the use of dopamine replacement therapy in the form of l-dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by l-dopa than by dopamine agonist drugs. This has been associated with the short duration of l-dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of l-dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD.     

Therapeutic strategies to prevent motor complications in Parkinson's disease

Dopaminergic treatment of Parkinson's disease (PD) leads to significant improvement in Parkinsonian features; however, the treatment response is hampered by the appearance of motor complications, including dyskinesias and motor fluctuations. These motor complications have a significant negative impact on quality-of-life. Therapeutic strategies using different types and timing of dopaminergic therapy may influence the emergence of motor complications. While sustained release preparations of levodopa have not shown benefit over immediate release preparations, the early combination of a dopamine agonist with levodopa appears to reduce the onset of motor fluctuations. An even larger body of evidence has found that initiating treatment with a dopamine receptor agonist (as compared to immediate release levodopa) is associated with a reduction in motor fluctuations, particularly dyskinesias. These data have led to evidence-based medicine evaluations indicating that the use of dopamine agonists is efficacious and clinically useful for the prevention of motor complications.     

Pathophysiology of Parkinson's disease

Parkinson's disease (PD) has classically been considered a disease of motor dysfunction, but it also includes psychiatric symptoms. To better understand the symptoms and signs that accompany PD, the interrelationships of deep brain structures and cortical areas involved with this neurodegenerative disease must be investigated.Current models of basal ganglia/cortical physiology attempt to integrate motor and nonmotor physiology and describe the pathophysiology attributable to PD. The cortical areas comprising basal ganglia/cortical loops include frontal structures involved in motor program as well as more prefrontal structures likely subserving non-motor functions such as cognition. The etiology of PD is not clear, but studies have implicated oxidative stress from exogenous stressors or endogenous neurotoxins. A large number of PD patients have been found to exhibit mitochondrial dysfunction. Lewy bodies are seen within dopaminergic and other neuronal populations affected in PD, and they stain positive for ubiquitin and alpha-synuclein. The small percentage of familial PD has often been found to coincide with dominantly inherited mutations in the gene for alpha-synuclein, or with the recessive gene mutation for parkin, which is involved in the ubiquitination pathway. Selected neuronal populations are affected in PD, and the neurodegeneration may include dopaminergic neurons outside the substantia nigra pars compacta, as well and non-dopaminergic neurons. The loss of these neuronal populations within the basal ganglia-frontal circuits can have a profound effect upon the motor and neurobehavioral symptoms in PD. L-dopa remains the most effective pharmacologic therapy for PD, however as the disease progresses, the drug loses its efficacy and troublesome sideeffects often occur. The renewal of surgical interventions for PD has increased the insight into the pathophysiology of PD,and surgical lesions have shown that motor and cognitive fronto-subcortical circuits are seemingly segregated in patients with PD. Investigation into these circuits helps provides models underlying motor and cognitive pathophysiology of PD.     

Pergolide in the treatment of patients with early and advanced Parkinson's disease

Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.     

Dopamine receptor agonists mediate neuroprotection in malonate-induced striatal lesion in the rat

Mitochondrial bioenergetic defects are involved in neurological disorders associated with neuronal damage in the striatum, such as Huntington's disease and cerebral ischemia. The striatal release of neurotransmitters, in particular dopamine, may contribute to the development of the neuronal damage. Recent studies have shown that dopamine agonists may exert neuroprotective effects via multiple mechanisms, including modulation of dopamine release from nigrostriatal dopaminergic terminals. In rats, intrastriatal injection of malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces a lesion similar to that observed following focal ischemia or in Huntington's disease. In this study, we used the malonate model to explore the neuroprotective potential of dopamine agonists. Sprague-Dawley rats were injected systemically with increasing concentrations of D(1), D(2), or mixed D(1)/D(2) dopamine agonists prior to malonate intrastriatal insult. Administration of increasing doses of the D(2)-specific agonist quinpirole resulted in increased protection against malonate toxicity. Conversely, the D(1)-specific agonist SKF-38393, as well as the mixed D(1)/D(2) agonist apomorphine, conferred higher neuroprotection at lower than at higher concentrations. Our data suggest that malonate-induced striatal toxicity can be attenuated by systemic administration of dopamine agonists, with D(1) and D(2) agonists showing different profiles of efficacy.     

Functional neuroimaging and repetitive transcranial magnetic stimulation in Parkinson's disease

Functional neuroimaging provides insights into the pathogenesis of motor symptoms in Parkinson's disease (PD) and improves our understanding of both established neuromodulatory therapies such as deep brain stimulation (DBS) and potential ones such as repetitive transcranial magnetic stimulation (rTMS). Functional imaging studies can reveal the consequences of the dopaminergic lesion in PD among a widespread network of subcortical-cortical regions. Characteristic patterns of normal cortical brain activation for motor tasks are systematically altered in PD. Recent work has emphasized the task dependence of these changes and their gradual evolution over the course of the disease. Clinically relevant PD treatment with medications or DBS tends to normalize these patterns. In this context, rTMS is discussed as a potential noninvasive alternative for neuromodulation of cortical function. Although rTMS is not a current treatment, we review recent rTMS studies in PD that suggest its promise, illustrate how functional imaging can guide application of rTMS, and suggest that subcortical dopamine release could be an rTMS mechanism of action. The combination of rTMS and functional neuroimaging broadens our knowledge of functional cortical networks in PD, which can eventually provide physicians with pathophysiologic information about different PD treatment options and rationales for neuromodulatory interventions.     

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 contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson's disease

Current research into Parkinson's disease (PD) is directed at developing novel agents and strategies for improved symptomatic management. The aim of this research is to provide effective and maintained symptom control throughout the course of the disease without loss of efficacy and without priming the basal ganglia for the onset of dyskinesia. To achieve these objectives, it is important to have relevant animal models of PD in which new pharmacological agents and treatment strategies can be assessed prior to clinical assessment. At present, the most effective experimental model of PD is the methyl phenyl tetrahydropyridine (MPTP)-treated primate. Primates treated with MPTP develop motor disturbances resembling those seen in idiopathic PD, including bradykinesia, rigidity and postural abnormalities. In addition, MPTP-treated primates are responsive to all commonly used antiparkinsonian agents and display treatment-associated motor complications such as dyskinesia, wearing-off and on-off, which occur during the long-term treatment of the illness.This review examines how studies conducted in MPTP-treated primates have contributed to the development of dopaminergic therapies. There is now accumulating evidence that the pulsatile manner in which short-acting agents stimulate striatal dopamine receptors is a key contributing factor to the priming of the basal ganglia for dyskinesia induction. It has been suggested that providing more continuous stimulation of dopamine receptors will avoid the development of motor complications, particularly dyskinesia. So far, the actions of all commonly used antiparkinsonian drugs assessed in MPTP-treated primates have proved to be highly predictive of drug action in PD. These primate studies have demonstrated that long-acting dopamine agonists and levodopa given in combination with a catechol-O-methyl transferase (COMT) inhibitor (to increase its relatively short half-life), induce significantly less dyskinesia than occurs with standard levodopa therapy.