Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the ...illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine‐ or haloperidol‐treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro‐striatal pathway, such as the classical 6‐hydroxydopamine (6‐OHDA) rat and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6‐OHDA‐lesioned rats with L‐DOPA has allowed for examination of the mechanisms responsible for treatment‐related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin‐based models of nigro‐striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP‐treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti‐parkinsonian medications have been shown to be effective, is undoubtedly the most clinically‐relevant of all available models. The MPTP‐treated primate develops clear dyskinesia when repeatedly exposed to L‐DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non‐dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug‐related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Functional models of Parkinson's disease (PD) have led to effective treatment for the motor symptoms. Toxin‐based models, such as the 6‐hydroxydopamine–lesioned rat and ...1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine–treated primate, have resulted in novel dopaminergic therapies and new therapeutic strategies. They have also been used to study processes underlying motor complications, particularly dyskinesia, and for developing pharmacological approaches to dyskinesia avoidance and suppression. Symptomatic models of PD based on nigrostriatal degeneration have a high degree of predictability of clinical effect of dopaminergic drugs on motor symptoms in humans. However, the effects of nondopaminergic drugs in these models do not translate effectively into clinical efficacy. Newer experimental models of PD have attempted to reproduce the pathogenic process and to involve all areas of the brain pathologically affected in humans. In addition, models showing progressive neuronal death have been sought but so far unsuccessfully. Pathogenic modeling has been attempted using a range of toxins, as well as through the use of transgenic models of gene defects in familial PD and mutant rodent strains. However, there are still no accepted progressive models of PD that mimic the processes known to occur during cell death and that result in the motor deficits, pathology, biochemistry, and drug responsiveness as seen in humans. Nevertheless, functional models of PD have led to many advances in treating the motor symptoms of the disorder, and we have been fortunate to have them available. They are an important reason the treatment of PD is so much better compared with treatments for related illnesses. Ann Neurol 2008;64 (suppl):S16–S29
Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment ...exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.
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► This review summarizes the key pathological and clinical features of Parkinson disease. ► The roles of genetics and predisposing and protective factors are highlighted. ► Currently known mechanisms of neurodegeneration are critically appraised. ► The current animal models of Parkinson disease are appraised. ► The difficulty of developing effective neuroprotective drugs when no good models exist is highlighted.
Abstract The MPTP-treated primate has proved to be a highly predictive model of the effects of dopaminergic drugs in the symptomatic treatment of Parkinson's disease (PD) and for the avoidance of ...motor complications. Using MPTP-treated primates, new dopaminergic therapies have been devised alongside novel treatment strategies and novel routes of administration while providing knowledge on how to use dopaminergic drugs in a manner that avoids the onset of motor complications. The use of MPTP-treated primates led to the concept of continuous dopaminergic stimulation (CDS) and the early introduction of dopamine receptor agonists as monotherapy for PD for the prevention of dyskinesia. However, CDS does not explain the differences in dyskinesia induction that exist between l -dopa and dopamine receptor agonists, and a more rationale approach to therapy involves continuous drug delivery (CDD). CDD has been explored in the MPTP-treated primate and this review focuses on some of the evidence showing that the delivery of dopaminergic drugs in PD is key to the avoidance of dyskinesia while maintaining therapeutic efficacy. Other types of motor complication, such as “wearing off” and “on–off” remain to be explored in MPTP-treated primates and the model has yet to be used to examine non-motor components of PD. Despite having been employed for almost 25 years, the MPTP-treated primate has many potential uses in the future that will further improve the treatment of PD.
Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of Parkinson's disease (PD). The basis of both is considered to be a reflection of ...the progression of neuronal degeneration, coupled with the nature of drug treatment used to control motor symptoms. The concept of continuous dopaminergic stimulation has been used to explain both the onset of wearing off and dyskinesia and their avoidance through pharmacologic manipulation. This review focuses on using with the transdermal dopamine agonist, rotigotine, for continuous dopaminergic drug delivery in the treatment of PD.
Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor ...symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects.
We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents.
Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time.
Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic–pituitary–adrenal axis.
•The adenosine A2A antagonist istradefylline is an anti-Parkinson's disease agent.•Istradefylline showed antidepressant-like action in animal models.•Istradefylline may be useful for the treatment of depression in Parkinson's disease.•Its effects might be attributable to modulation of HPA axis.
Concepts of pathogenesis in Parkinson's disease (PD) have been based on attempts to understand the mechanisms responsible for nigral dopaminergic cell death. Pathogenesis has been proposed to involve ...oxidative and nitrative stress, excitotoxicity, inflammation, mitochondrial dysfunction, and altered proteolysis. These processes are considered to form a complex cascade of interrelated events that lead to neuron death by way of apoptosis. However, current views on pathogenic mechanisms in PD may not be as exact as commonly proposed. Future concepts of pathogenesis in PD need to incorporate events leading to the destruction of non-dopaminergic nuclei and to distinguish between primary factors that are responsible for disease initiation and secondary factors that contribute to disease progression. Importantly, there is a need to determine whether PD is a single illness with a common pathogenesis or a group of related illnesses with different pathogenic mechanisms. This is an essential step to understanding pathogenesis and is critical to the development of comprehensive neuroprotective approaches to treatment.
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A ...receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.
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