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Parkinson Disease: HELP
Articles by Peter Jenner
Based on 42 articles published since 2008
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Between 2008 and 2019, P. Jenner wrote the following 42 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial A glimmer of light at the end of the tunnel? 2017

Jenner, Peter. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Health Sciences and Medicine, King's College, London, United Kingdom. ·Mov Disord · Pubmed #28921664.

ABSTRACT: -- No abstract --

2 Review Nonmotor Symptoms in Experimental Models of Parkinson's Disease. 2017

Titova, Nataliya / Schapira, Anthony H V / Chaudhuri, K Ray / Qamar, Mubasher A / Katunina, Elena / Jenner, Peter. ·Federal State Budgetary Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia. Electronic address: nattitova@yandex.ru. · UCL Institute of Neurology, London, United Kingdom. · National Parkinson Foundation International Centre of Excellence, King's College London and King's College Hospital, London, United Kingdom; The Maurice Wohl Clinical Neuroscience Institute, King's College London, National Institute for Health Research (NIHR) South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom. · Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. ·Int Rev Neurobiol · Pubmed #28802936.

ABSTRACT: Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric, cognitive to sleep and sensory disorders and can arise from the disease process as well as from drug treatment. The clinical heterogeneity of nonmotor symptoms of PD is underpinned by a wide range of neuropathological and molecular pathology, affecting almost the entire range of neurotransmitters present in brain and the periphery. Understanding the neurobiology and pathology of nonmotor symptoms is crucial to the effective treatment of PD and currently a key unmet need. This bench-to-bedside translational concept can only be successful if robust animal models of PD charting the genesis and natural history of nonmotor symptoms can be devised. Toxin-based and transgenic rodent and primate models of PD have given us important clues to the underlying basis of motor symptomatology and in addition, can provide a snapshot of some nonmotor aspects of PD, although the data are far from complete. In this chapter, we discuss some of the nonmotor aspects of the available experimental models of PD and how the development of robust animal models to understand and treat nonmotor symptoms needs to become a research priority.

3 Review Two hundred years since James Parkinson's essay on the shaking palsy-Have we made progress? Insights from the James Parkinson's 200 years course held in London, March 2017. 2017

Chaudhuri, K Ray / Jenner, Peter. ·National Parkinson Foundation International Centre of Excellence, King's College London and King's College Hospital, London, UK. · Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. · Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, UK. ·Mov Disord · Pubmed #28799259.

ABSTRACT: -- No abstract --

4 Review Non-motor features of Parkinson disease. 2017

Schapira, Anthony H V / Chaudhuri, K Ray / Jenner, Peter. ·Department of Clinical Neurosciences, University College London (UCL) Institute of Neurology, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. · National Parkinson Foundation International Centre of Excellence, King's College Hospital, King's College London, Camberwell Road, London SE5 9RS, UK. · Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, Newcomen Street, London SE1 1UL, UK. ·Nat Rev Neurosci · Pubmed #28592904.

ABSTRACT: Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.

5 Review New Symptomatic Treatments for the Management of Motor and Nonmotor Symptoms of Parkinson's Disease. 2017

Taddei, Raquel N / Spinnato, Federica / Jenner, Peter. ·King's College London and King's College Hospital, London, United Kingdom. Electronic address: raqueltaddei@hotmail.com. · University of Palermo, Faculty of Medicine, Palermo, Italy. · Institute of Pharmaceutical Science, King's College London, London, United Kingdom. ·Int Rev Neurobiol · Pubmed #28554417.

ABSTRACT: Motor symptoms are core features of Parkinson's disease, while nonmotor symptoms are present from the prodromal stage. Management strategies for the motor symptoms of Parkinson's disease have been widely researched and there have been many advances. Therapy has evolved from oral therapy to once a day to nonoral strategies, both for rescue and for infusion therapy. Treatment for nonmotor symptoms, however, has remained a key unmet need, although of late evidence base for management of some nonmotor symptoms such as pain, dementia, aspects of sleep dysfunction, and constipation has emerged. However, management of many nonmotor symptoms such as anxiety, apathy, fatigue, and insomnia remains uncharted. In this review, we address these management strategies and discuss the evidence base of available therapies.

6 Review Hallmarks of Treatment Aspects: Parkinson's Disease Throughout Centuries Including l-Dopa. 2017

Kim, Hee J / Jeon, Beom S / Jenner, Peter. ·Konkuk University School of Medicine, Seoul, South Korea; Parkinson Disease Study Group, Seoul National University Hospital, Seoul, South Korea. · Parkinson Disease Study Group, Seoul National University Hospital, Seoul, South Korea; Movement Disorder Center, Neuroscience Research Institute, College of Medicine, Seoul National University, Seoul, South Korea. Electronic address: brain@snu.ac.kr. · Institute of Pharmaceutical Science, King's College London, London, United Kingdom. ·Int Rev Neurobiol · Pubmed #28554412.

ABSTRACT: Deficit of striatal dopamine was first discovered in postmortem brain of patients with Parkinson's disease in 1960. This observation was the starting point for dopamine replacement therapy, and successful introduction of high dose l-dopa therapy in the 1969 revolutionized the treatment of Parkinson's disease. Since then, constant attempts have been made to enhance the efficacy of l-dopa and reduce motor complications by providing more continuous dopamine stimulation. This chapter traces the hallmarks of medical treatments for Parkinson's disease throughout centuries including the first description of antiparkinsonian effects of anticholinergics, the birth of apomorphine in the 1900s, then discovery of l-dopa in the 1960s, and development of dopamine agonists since the 1970s.

7 Review Apomorphine - pharmacological properties and clinical trials in Parkinson's disease. 2016

Jenner, Peter / Katzenschlager, Regina. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Life Science and Medicine, King's College London, London, UK. Electronic address: peter.jenner@kcl.ac.uk. · Department of Neurology and Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Danube Hospital, Vienna, Austria. Electronic address: regina.katzenschlager@wienkav.at. ·Parkinsonism Relat Disord · Pubmed #27979722.

ABSTRACT: Apomorphine is often considered an archetypal dopamine agonist used in the treatment of Parkinson's disease (PD). However, it can be clearly differentiated from most other commonly used dopamine agonists on the basis of its pharmacology and on its unique clinical profile. Like levodopa and dopamine, apomorphine acts as a potent, direct and broad spectrum dopamine agonist activating all dopamine receptor subtypes. It also has affinity for serotonin receptors, and α-adrenergic receptors. Apomorphine is usually titrated to a dose that provides an equivalent antiparkinsonian response to that provided by levodopa, and its subcutaneous delivery allows a rapid onset of action, usually within 7-10 min. The mode of apomorphine delivery impacts on its clinical profile so as to provide two very different approaches to therapy in PD. When administered as an acute subcutaneous injection, it induces reliable and rapid relief from OFF periods underscoring its utility as a rescue medication. When given as a subcutaneous infusion, it significantly improves overall daily OFF time and there is also evidence to suggest that, in those patients who replace most or all of their oral drugs with apomorphine infusion, dyskinesia may also improve. In this paper, we review the rich pharmacology of apomorphine and review its efficacy in PD based on data from clinical trials.

8 Review Non motor subtypes and Parkinson's disease. 2016

Sauerbier, Anna / Jenner, Peter / Todorova, Antoniya / Chaudhuri, K Ray. ·National Parkinson Foundation International Centre of Excellence, King's College London, London, UK; National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and The Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. · Institute of Pharmaceutical Science, King's College London, UK. · National Parkinson Foundation International Centre of Excellence, King's College London, London, UK; National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and The Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. Electronic address: ray.chaudhuri@kcl.ac.uk. ·Parkinsonism Relat Disord · Pubmed #26459660.

ABSTRACT: Non motor symptoms (NMS) represent a significant burden in Parkinson's disease (PD) with numerous studies highlighting the importance of NMS both in "pre-motor" phase of PD as well as throughout the course of disease. In part this has led the international Parkinson and Movement Disorder Society (IPMDS) task force to attempt a re-definition of PD incorporating NMS and not base the diagnosis solely on motor symptoms. While motor subtypes within PD have been recognized and researched, recent clinical and neurobiological research suggests the existence of discrete non motor subtypes in PD, particularly in untreated (drug naïve) and early PD patients. Several independent observers have reported specific "clusters of NMS dominant PD" using a data driven approach in early and untreated PD patients while others have reported on the burden of NMS in untreated PD and specific NMS dominant phenotypes in untreated or treated PD using observational case series based data. In this review we report on specific NMS dominant phenotypes of PD as described in the literature using clinical observational studies and address pathophysiological concepts. A proposal for several NMS subtypes are reported combining clinical reports with, where possible, evidence base supporting probable biomarkers.

9 Review An overview of adenosine A2A receptor antagonists in Parkinson's disease. 2014

Jenner, Peter. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, United Kingdom. Electronic address: peter.jenner@kcl.ac.uk. ·Int Rev Neurobiol · Pubmed #25175961.

ABSTRACT: Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of Parkinson's disease (PD) through a non-dopaminergic mechanism. As a class, adenosine A2A antagonists are effective in reversing motor deficits in haloperidol-treated rodents, 6-OHDA-lesioned rats, and MPTP-treated primates when combined with low doses of l-dopa or dopamine agonist drugs. Importantly, they improve motor function without worsening dyskinesia and they may prevent the onset of involuntary movements. Adenosine A2A receptor antagonists are active in animal models of reduced cognition, anxiety, and depression and so this drug class may also be effective in controlling the neuropsychiatric components of nonmotor symptoms in PD. Preclinical evidence has shown that A2A antagonists can prevent neuronal loss in experimental models of PD and their disease modifying activity needs to be explored in man. Importantly, a number of A2A antagonists have been studied in PD in clinical trial for their effects on motor function. So far, little evidence has emerged of an effect of monotherapy with adenosine antagonists in early PD. However, in later stage, patient populations already treated with dopaminergic drugs but exhibiting "wearing off," adenosine antagonists have been demonstrated to reduce "off" time without increasing troublesome dyskinesia in phase IIB trials. However, in larger phase III evaluations, a consistent significant decrease in "off" time has proved more difficult to demonstrate-due in part to trial conduct. So far, only istradefylline has completed phase III development and it is now marketed for the treatment of PD. Adenosine A2A antagonists are the first non-dopaminergic approach to the treatment of PD to appear in the recent era. They represent a novel way of approaching therapy that will provide additional benefit to that achieved with dopaminergic medication, while avoiding common side effects and may in addition, improve some nonmotor symptoms of PD that are currently poorly treated.

10 Review Non-motor Parkinson's: integral to motor Parkinson's, yet often neglected. 2014

Todorova, Antoniya / Jenner, Peter / Ray Chaudhuri, K. ·Department of Neurology, National Parkinson Foundation Centre of Excellence, King's College Hospital, and Kings College, London, UK. · Institute of Pharmaceutical Science, King's College London, London, UK. ·Pract Neurol · Pubmed #24699931.

ABSTRACT: Non-motor symptoms are a key component of Parkinson's disease, possibly representing a clinical biomarker of its premotor phase. The burden of non-motor symptoms can define a patient's health-related quality of life. Non-motor symptoms substantially increase the cost of care-requiring increased hospitalisation and treatment-and pose a major challenge to healthcare professionals. However, clinicians often regard non-motor symptoms and their management as peripheral to that of the motor symptoms. Here, we address the clinical issues and unmet needs of non-motor symptoms in Parkinson's disease.

11 Review Current development of acupuncture research in Parkinson's disease. 2013

Zeng, Bai-Yun / Salvage, Sarah / Jenner, Peter. ·Neurodegenerative Disease Research Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, London, United Kingdom. Electronic address: b.zeng@kcl.ac.uk. ·Int Rev Neurobiol · Pubmed #24215921.

ABSTRACT: Parkinson's disease is an age-related progressive neurodegenerative disease. The etiology and pathogenetic mechanisms that cause PD are still not fully understood. The available treatments to PD are only symptomatic relief. Acupuncture is used to treat many medical conditions for 1000 years in China and has gained wider and increasing acceptance within both public and medical profession because it has been a very safe and well-tolerated treatment. In this chapter, we reviewed relevant laboratory findings regarding acupuncture mechanism on Parkinson's. We showed that acupuncture stimulation in Parkinson's models had generated valuable mechanistic insight of Parkinson's and showed that acupuncture treatment is in fact a neuroprotective therapy that increase the release of various neuroprotective agents such as brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and cyclophilin A. In addition, acupuncture therapy slows cell death process and attenuates oxidative stress to dopaminergic neurons in the substantia nigra. Further, acupuncture therapy modulates neuronal activity of the basal ganglia output structures. These results suggest that early application of acupuncture therapy to Parkinson's patients may be helpful for the best efficacy of acupuncture treatment. It is hopeful that translation of achievement in acupuncture research in Parkinson's models will maximize the potentials of acupuncture treatment.

12 Review Parkinson's disease--the debate on the clinical phenomenology, aetiology, pathology and pathogenesis. 2013

Jenner, Peter / Morris, Huw R / Robbins, Trevor W / Goedert, Michel / Hardy, John / Ben-Shlomo, Yoav / Bolam, Paul / Burn, David / Hindle, John V / Brooks, David. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·J Parkinsons Dis · Pubmed #23938306.

ABSTRACT: The definition of Parkinson's disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article--widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic perspective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include--Parkinson's syndrome, Parkinson's syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).

13 Review Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson's disease. 2013

Jenner, Peter. ·Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·Neurol Clin · Pubmed #23931952.

ABSTRACT: 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.

14 Review Pathogenesis of Parkinson's disease. 2013

Hirsch, Etienne C / Jenner, Peter / Przedborski, Serge. ·Université Pierre et Marie Curie-Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moëlle Épinière, Hôpital de la Salpêtrière, Paris, France. ·Mov Disord · Pubmed #22927094.

ABSTRACT: Parkinson's disease is a common adult-onset neurodegenerative disorder whose pathogenesis remains essentially unknown. Currently, it is believed that the neurodegenerative process in Parkinson's disease is a combination of both cell-autonomous and non-cell-autonomous mechanisms. Proposed cell-autonomous mechanisms include alterations in mitochondrial bioenergetics, dysregulation of calcium homeostasis, and impaired turnover of mitochondria. As for the proposed non-cell-autonomous mechanisms, they involve prion-like behavior of misfolded proteins and neuroinflammation. This suggests that cell death in Parkinson's disease is caused by a multifactorial cascade of pathogenic events and argues that effective neuroprotective therapy for Parkinson's disease may have to rely on multiple drug interventions.

15 Review Moving from continuous dopaminergic stimulation to continuous drug delivery in the treatment of Parkinson's disease. 2012

Gershanik, O / Jenner, P. ·Institute of Neuroscience, Favaloro Foundation University Hospital, Buenos Aires, Argentina. ogershanik@ffavaloro.org ·Eur J Neurol · Pubmed #22221452.

ABSTRACT: Motor fluctuations and motor complications are a major consequence of the treatment and progression of Parkinson's disease (PD) and they have, in particular, been linked to L-dopa therapy. Using continuous dopaminergic stimulation (CDS) by employing longer acting dopaminergic drugs has been proposed as a means of avoiding or lowering their occurrence. However, both the preclinical and clinical evidence base suggest that this concept does not fully explain the differences between L-dopa and dopamine (DA) agonist drugs and that their pharmacological profiles may also be important. In addition, the way in which drugs are delivered in PD appears to have a marked influence on both efficacy and side-effect profile. As a consequence, the concept of continuous drug delivery (CDD) has arisen to explain the differences between the intermittent and continuous delivery of both L-dopa and DA agonists. This review presents the evidence for using CDD as a working concept for the early and later stages of PD and in the treatment of motor complications and motor fluctuations. CDD as an approach to the treatment of PD may improve the outcome of therapy and explain the differences between drug classes and the delivery systems employed.

16 Review Striatal plasticity in Parkinson's disease and L-dopa induced dyskinesia. 2012

Iravani, M M / McCreary, A C / Jenner, P. ·Neurodegenerative Diseases Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. ·Parkinsonism Relat Disord · Pubmed #22166408.

ABSTRACT: Striatal function adapts to the loss of nigrostriatal dopaminergic input in Parkinson's disease (PD) to initially maintain voluntary movement, but subsequently changes in response to drug treatment leading to the onset of motor complications, notably dyskinesia. Alterations in presynaptic dopaminergic function coupled to changes in the response of post-synaptic dopaminergic receptors causing alterations in striatal output underlie attempts at compensation and the control of movement in early PD. However, eventually compensation fails and persistent changes in striatal function ensue that involve morphological, biochemical and electrophysiological change. Key alterations occur in cholinergic and glutamatergic transmission in the striatum and there are changes in motor programming controlled by events involving LTP/LTD. Dopamine replacement therapy with L-dopa modifies altered striatal function and restores motor function but non-physiological dopamine receptor stimulation leads to altered signalling through D1 and D2 receptor systems and changes in striatal function causing abnormalities of LTP/LTD mediated through glutamatergic/nitric oxide (NO) mechanisms. These lead to the onset of dyskinesia and underlie the priming process that characterise dyskinesia and its persistence.

17 Review Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. 2011

Jenner, Peter / Langston, J William. ·Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·Mov Disord · Pubmed #21953831.

ABSTRACT: The ADAGIO study demonstrated a symptomatic benefit for rasagiline in early Parkinson's disease (PD) and suggested a disease-modifying effect. Evidence indicates that mitochondrial dysfunction plays a role in the pathogenesis of PD and that this may be the site of effect for rasagiline. In this systematic review, evidence for the role of mitochondria in the pathogenesis of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and the actions of rasagiline and its component parts, namely propargylamine and the metabolite, aminoindan. Evidence for the role of mitochondria in the pathogenesis and treatment of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and clinical actions of rasagiline. Monoamine oxidase B (MAO-B) located in the outer mitochondrial membrane controls dopamine metabolism in early PD, and this is the likely location for the symptomatic action of rasagiline. Accumulating evidence indicates that mitochondrial impairment contributes to dopaminergic neuronal loss in PD, either directly or through other mechanisms such as oxidative stress or protein misfolding. Further rasagiline affects numerous mitochondrial mechanisms that prevent apoptotic cell death including prevention of opening of the mitochondrial transition pore, decreased release of cytochrome C, alterations in pro-antiapoptotic genes and proteins, and the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Thus, the functional neuroprotective actions of rasagiline may not be dependent on MAO-B inhibition, but rather may involve actions of the propargylamine moiety and the aminoindan metabolite. An accumulating body of literature indicates a mitochondrial site of action for rasagiline and highlights the neuroprotective action of the drug, providing strong biological plausibility for disease-modifying effects of the drug such as those observed in ADAGIO.

18 Review New approaches to therapy. 2011

Brotchie, Jonathan / Jenner, Peter. ·University Health Network, Toronto Western Research Institute, Toronto M5T 2S8, Ontario, Canada. ·Int Rev Neurobiol · Pubmed #21907085.

ABSTRACT: L-DOPA-induced dyskinesia (LID) is a major complication of the treatment of Parkinson's disease (PD). LID comprises two major components, the priming process responsible for its onset and the expression of involuntary movements that underlies its clinical manifestation. The mechanisms responsible for these components are partially understood and their biochemical basis is being unraveled but avoidance and treatment remain an issue. In this chapter, we review what is known about the involvement of dopaminergic systems in LID and the way in which dopaminergic therapy can be used to avoid the onset of LID or to reverse or suppress involuntary movements once these have been established. The involvement of specific dopamine receptor subtypes, continuous dopaminergic stimulation (CDS) and continuous drug delivery (CDD) is reviewed. However, a major role is emerging in the avoidance and suppression of LID through the use of nondopaminergic mechanisms and we consider the present and future use of glutamatergic drugs, serotoninergic agents, adenosine antagonists and others as a means of improving therapy. There is compelling basic science supporting a role for nondopaminergic approaches to LID but at the moment the translational benefit to PD is not being achieved as predicted. There needs to be further consideration of why this is the case and how in future, both experimental models of dyskinesia and clinical trial design can be optimized to ensure success.

19 Review Mechanisms underlying the onset and expression of levodopa-induced dyskinesia and their pharmacological manipulation. 2011

Iravani, Mahmoud M / Jenner, Peter. ·Neurodegenerative Disease Research Centre, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. m.iravani@kcl.ac.uk ·J Neural Transm (Vienna) · Pubmed #21881839.

ABSTRACT: A significant proportion of patients with Parkinson's disease (PD) receiving dopamine replacement therapy in the form of levodopa develop dyskinesia that becomes a major complicating factor in treatment. Dyskinesia can only be effectively treated by a reduction in drug dose, which limits efficacy, by co-administration of the weak NMDA antagonist amantadine or by surgical treatment (pallidotomy, DBS). This raises the important question of why dyskinesia occurs in PD and how it can be avoided or suppressed by pharmacological treatment. This review assesses some of the mechanisms that underlie dyskinesia induction and expression from presynaptic changes in dopaminergic neurones to postsynaptic alterations in basal ganglia function and examines potential approaches to prevention and treatment. These include glutamatergic approaches where agents that directly or indirectly alter glutamatergic neurotransmission modify the intracellular influx of Ca(2+) and reduce the formation of nitric oxide by neuronal nitric oxide synthase that may form an integral component of the complex cascade of events leading to dyskinesia. There is increasing evidence for the role of serotoninergic neurones in dyskinesia induction related to non-physiological formation and release of dopamine and serotoninergic agonists can modify dyskinesia expression. Similarly, noradrenergic receptors may serve to alter dyskinesia intensity and α-2-adrenoceptor antagonists alter the expression of levodopa-induced dyskinesia in both experimental models of PD and in man. Finally, other potential approaches to dyskinesia treatment based on manipulation of opiate, cannabinoid, adenosine and histamine receptors are considered. The conclusion is that the cause of levodopa-induced dyskinesia remains to be fully elucidated and that new approaches to treatment through non-dopaminergic mechanisms are required to control the onset and expression of involuntary movements.

20 Review Continuous drug delivery in early- and late-stage Parkinson's disease as a strategy for avoiding dyskinesia induction and expression. 2011

Jenner, P / McCreary, A C / Scheller, D K A. ·Neurodegenerative Disease Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King's College, London, UK. peter.jenner@kcl.ac.uk ·J Neural Transm (Vienna) · Pubmed #21881838.

ABSTRACT: 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.

21 Review Etiology and pathogenesis of Parkinson's disease. 2011

Schapira, Anthony H / Jenner, Peter. ·Department of Clinical Neurosciences, Institute of Neurology, University College, London, United Kingdom. peter.jenner@kcl.ac.uk ·Mov Disord · Pubmed #21626550.

ABSTRACT: The past 25 years have seen a major expansion of knowledge concerning the cause of Parkinson's disease provided by an understanding of environmental and genetic factors that underlie the loss of nigral dopaminergic neurons. Based on the actions of toxins, postmortem investigations, and gene defects responsible for familial Parkinson's disease, there is now a general consensus about the mechanisms of cell death that contribute to neuronal loss in Parkinson's disease. Mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammatory change are considered to lead to cell dysfunction and death by apoptosis or autophagy. Ageing is the single most important risk factor for Parkinson's disease, and the biochemical changes that are a consequence of aging amplify these abnormalities in Parkinson's disease brain. What remains to be determined is the combination and sequence of events leading to cell death and whether this is identical in all brain regions where pathology occurs and in all individuals with Parkinson's disease. Focusing on those events that characterize Parkinson's disease, namely, mitochondrial dysfunction and Lewy body formation, may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.

22 Review Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease. 2011

Duty, Susan / Jenner, Peter. ·King's College London, Wolfson Centre for Age-Related Disease, London, UK. susan.duty@kcl.ac.uk ·Br J Pharmacol · Pubmed #21486284.

ABSTRACT: 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.

23 Review When do levodopa motor fluctuations first appear in Parkinson's disease? 2010

Stocchi, Fabrizio / Jenner, Peter / Obeso, Jose A. ·Institute of Neurology, IRCCS San Raffaele Pisana, Rome, Italy. fabrizio.stocchi @ sanraffaele.it ·Eur Neurol · Pubmed #20332641.

ABSTRACT: Although levodopa provides therapeutic benefit over the entire course of Parkinson's disease, most patients eventually notice a decline in the duration of benefit from each dose, a phenomenon termed 'wearing-off' or 'end of dose' deterioration. This is an important indicator that the patient is entering a more complex phase of the disease. Wearing-off has been classically associated with the later stages of Parkinson's disease, but it is becoming apparent that patients with early disease, presenting as well controlled, may already be experiencing fluctuations in their response to levodopa. However, neither the pathophysiology nor the clinical relevance of the early emergence of wearing-off has been properly explored. We now review the preclinical and clinical evidence that suggests that even patients who are apparently still in the honeymoon phase of drug treatment may have early fluctuations in their motor response to dopaminergic therapy. It is important that early wearing-off is recognized as it has important consequences for the long-term outcome and for the medication regimens to be used.

24 Review From the MPTP-treated primate to the treatment of motor complications in Parkinson's disease. 2009

Jenner, Peter. ·Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College London, London, UK. peter.jenner@kcl.ac.uk ·Parkinsonism Relat Disord · Pubmed #20123550.

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.

25 Review Perspectives on recent advances in the understanding and treatment of Parkinson's disease. 2009

Schapira, A H / Agid, Y / Barone, P / Jenner, P / Lemke, M R / Poewe, W / Rascol, O / Reichmann, H / Tolosa, E. ·Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK. a.schapira@medsch.ucl.ac.uk ·Eur J Neurol · Pubmed #19723294.

ABSTRACT: There have been numerous important recent advances in our understanding of the causes of Parkinson's disease (PD), the treatments available and how these are best applied for the long-term management of patients. Novel genes causing familial PD have been discovered and mechanisms leading to cell dysfunction and death identified. The PD prodrome is now a subject of great interest and clinical markers are being defined that may in future, together with biochemical markers, support an early, pre-motor diagnosis of PD. This will become important as new therapies are developed to modify disease progression. In the interim, the optimization of existing therapies remains an important priority. The value of existing and novel continuous drug delivery systems in PD is seen as providing simplified regimens, maintenance of motor control, reduction in motor complications and improved patient adherence to drug use.

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