Parkinson Disease: Jenner P

Jenner P. · Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom. · Ann Neurol. · Pubmed #19127585 No free full text.

Abstract: 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.

Jenner P. · Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom. · Mov Disord. · Pubmed #18781676 No free full text.

Abstract: Dyskinesia affects approximately 30 to 40% of patients with Parkinson's disease but treatment options for the prevention of dyskinesia induction and for the suppression of established dyskinesia are limited. This situation is made more difficult by a poor understanding of the pathphysiology of the processes underlying both the priming for dyskinesia and the manifestations of involuntary movements. Loss of tonic stimulation of striatal dopamine receptors in PD and its replacement by pulsatile dopaminergic stimulation using short acting drugs has been proposed as leading to the abnormalities that cause dyskinesia induction. As a consequence, the concept of continuous dopaminergic stimulation (CDS) was introduced to explain why longer acting dopamine agonists do not produce the same intensity of dyskinesia. Key to these ideas has been the use of both 6-OHDA lesioned rodent models of PD and, in particular MPTP-treated primates. Comparison of the ability to induce dyskinesia of the same dopamine agonists given by pulsatile or continuous administration or more constant administration of Levodopa (L-dopa) has shown that constant drug delivery (CDD) dramatically reduces dyskinesia induction. Similar conclusions have been reached from clinical investigations in PD. Recent studies in MPTP-treated primates have also suggested that switching from pulsatile drug delivery to CDD can be utilized to inhibit dyskinesia expression. However, CDS does explain some important features of dyskinesia induction in PD but it may not apply to early PD when remaining dopaminergic neurones buffer against pulsatile stimulation. In addition, CDS may not apply when comparing between drug classes and it appears that it is CDD which is more important in regulating therapeutic efficacy. Recently, studies in MPTP-treated primates have suggested that a range of nondopaminerigic drugs might be useful in suppressing dyskinesia. These have included 5-HT-1A agonists and alpha-2 adrenergic antagonists and a variety of other molecular entities. Unfortunately, these findings are not always reproducible in the same models and do not translate into clinically useful effects. Preclinical studies have suggested a number of directions that might be utilized to prevent dyskinesia in PD. However, much of what is proposed is empirically-based and we still do not have a good understanding of why dyskinesia appears, why it persists or how to bring the movements under control. Certainly, the use of CDD can reduce dyskinesia intensity but other factors also influence its appearance and it is these that we need to study at the preclinical level if effective therapies are to be developed.

Jenner P. · King's College London, Guy's Campus, School of Health and Biomedical Sciences, London SE1 1UL, UK. · Nat Rev Neurosci. · Pubmed #18714325 No free full text.

Abstract: L-DOPA (L-3,4-dihydroxyphenylalanine) remains the most effective drug for the treatment of Parkinson's disease. However, chronic use causes dyskinesia, a complex motor phenomenon that consists of two components: the execution of involuntary movements in response to drug administration, and the 'priming' phenomenon that underlies these movements' establishment and persistence. A reinterpretation of recent data suggests that priming for dyskinesia results from nigral denervation and the loss of striatal dopamine input, which alters glutamatergic synaptic connectivity in the striatum. The subsequent response of the abnormal basal ganglia to dopaminergic drugs determines the manner and timing of dyskinesia expression. The combination of nigral denervation and drug treatment establishes inappropriate signalling between the motor cortex and the striatum, leading to persistent dyskinesia.

Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17483689 No free full text.

Abstract: We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors. Although there is extensive new information on the etiology and pathogenesis of PD, which may advance its treatment, new syntheses of this information are needed. The second part of this two-part, state-of-the-art review by leaders in PD research critically examines the research field to identify areas for which new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part II are genetics, animal models, and oxidative stress.

Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D, Price DL. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17413315 No free full text.

This publication has no abstract.

Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, Hengerer B, Hirsch E, Jenner P, Le Novère N, Obeso JA, Schwarzschild MA, Spampinato U, Davidai G. · University Department of Clinical Neurosciences, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. · Nat Rev Drug Discov. · Pubmed #17016425 No free full text.

Abstract: Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinson's disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinson's disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinson's disease, and also for the motor complications that arise from the use of existing therapies.

Hurley MJ, Jenner P. · Neurodegenerative Diseases Research Group, School of Biomedical and Health Sciences, King's College London, SE1 1UL, United Kingdom. · Pharmacol Ther. · Pubmed #16458973 No free full text.

Abstract: Since the introduction of dopamine replacement therapy using L-3,4-dihydroxyphenyalanine (L-DOPA) to treat Parkinson's disease and the recognition of the problems associated with L-DOPA use, numerous studies have investigated dopamine receptor regulation and function in Parkinson's disease. These studies have provided insight into the pathological process of the disorder and the molecular consequences of chronic dopaminergic treatment, but they have been less successful in identifying new pharmacological targets or treatment regimes that are as effective as L-DOPA at alleviating the symptoms of Parkinson's disease. This review will present a summary of the reported changes in dopamine receptor regulation and function that occur in Parkinson's disease and will discuss their contribution to the current pharmacological management of Parkinson's disease.

Jenner P. · Neurodegenerative Diseases Research Centre, GKT School of Biomedical Sciences, King's College, London SE1 1UL, UK. · Expert Opin Investig Drugs. · Pubmed #16004599 No free full text.

Abstract: Dopamine replacement therapy effectively treats the early motor symptoms of Parkinson's disease (PD). However, its association with the development of motor complications limits its usefulness in late stages of the disease. Adenosine A(2A) receptors are localised to the indirect striatal output function and control motor behaviour. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD. Istradefylline is a novel adenosine A(2A) receptor antagonist currently in Phase III clinical trials for efficacy in patients with PD; results from Phase II clinical trials demonstrated that it provides a clinically meaningful reduction in 'off' time and an increased 'on' time with non-troublesome dyskinesia in levodopa-treated patients with established motor complications, and is safe and well tolerated.

Castro A, Valldeoriola F, Linazasoro G, Rodriguez-Oroz MC, Stochi F, Marin C, Rodriguez M, Vaamonde J, Jenner P, Alvarez L, Pavon N, Macias R, Luquin MR, Hernandez B, Grandas F, Gimenez-Roldan S, Tolosa E, Obeso JA. · Servicio de Neurología, Hospital Xeral de Galicia, Santiago de Compostela. · Neurologia. · Pubmed #15891947 links to  free full text

Abstract: Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Jenner P. · Neurodegenerative Diseases Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom. · Neurology. · Pubmed #15477581 No free full text.

This publication has no abstract.

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, Damier P, De Yebenes J, Gershanik O, Guttman M, Grandas F, Hallett M, Hornykiewicz O, Jenner P, Katzenschlager R, Langston WJ, LeWitt P, Melamed E, Mena MA, Michel PP, Mytilineou C, Obeso JA, Poewe W, Quinn N, Raisman-Vozari R, Rajput AH, Rascol O, Sampaio C, Stocchi F. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mov Disord. · Pubmed #15372588 No free full text.

Abstract: Levodopa is the most effective symptomatic agent in the treatment of Parkinson's disease (PD) and the "gold standard" against which new agents must be compared. However, there remain two areas of controversy: (1) whether levodopa is toxic, and (2) whether levodopa directly causes motor complications. Levodopa is toxic to cultured dopamine neurons, and this may be a problem in PD where there is evidence of oxidative stress in the nigra. However, there is little firm evidence to suggest that levodopa is toxic in vivo or in PD. Clinical trials have not clarified this situation. Levodopa is also associated with motor complications. Increasing evidence suggests that they are related, at least in part, to the short half-life of the drug (and its potential to induce pulsatile stimulation of dopamine receptors) rather than to specific properties of the molecule. Treatment strategies that provide more continuous stimulation of dopamine receptors provide reduced motor complications in MPTP monkeys and PD patients. These studies raise the possibility that more continuous and physiological delivery of levodopa might reduce the risk of motor complications. Clinical trials to test this hypothesis are underway. We review current evidence relating to these areas of controversy.

Jenner P. · Neurodegenerative Diseases Research Centre, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, UK. · Curr Opin Neurol. · Pubmed #15180131 No free full text.

Abstract: 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.

Jenner P. · Neurodegenerative Diseases Research Centre, Guy's King's and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom. · Neurology. · Pubmed #14718680 No free full text.

Abstract: Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.

Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, Koga K, Koike N, Kurokawa M, Kuwana Y, Mori A, Nakamura J, Nonaka H, Ochi M, Saki M, Shimada J, Shindou T, Shiozaki S, Suzuki F, Takeda M, Yanagawa K, Richardson PJ, Jenner P, Bedard P, Borrelli E, Hauser RA, Chase TN, Anonymous00418. · Kyowa Hakko Kogyo Co. Ltd., Tokyo, Japan. · Neurology. · Pubmed #14663020 No free full text.

Abstract: Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Jenner P. · Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, UK. · Neurology. · Pubmed #14663007 No free full text.

Abstract: The future management of Parkinson's disease (PD) requires pharmacologic agents that do not lose efficacy with disease progression or induce dyskinesia and that are free of other dopaminergic side effects. A2A receptor antagonists may provide an opportunity to introduce nondopaminergic management of PD. A2A receptors are selectively localized in basal ganglia and to the indirect output pathway where they control GABA and acetylcholine release. The A2A antagonists are effective in rodent models of PD, reversing motor deficits in haloperidol-treated, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, or reserpinized mice, and potentiating L-dopa-induced rotation in 6-hydroxydopamine-lesioned rats without inducing dyskinesia. Importantly, the selective A2A antagonist KW6002 reverses motor disability and increases locomotor activity in MPTP-treated primates without provoking dyskinesia established by previous exposure to L-dopa. In addition, KW6002 shows additive antiparkinsonian activity with L-dopa and the D2 agonist quinpirole in MPTP-treated primates without enhancing the intensity of dyskinesia. The data available suggest that A2A antagonists, such as KW6002, may be effective as monotherapy for the management of PD and that they will also produce additional benefit when administered in combination with L-dopa or dopamine agonist therapy.

Jenner P. · Neurodegenerative Diseases Research Centre, GKT School of Biomedical Sciences, King's College, London, United Kingdom. · Ann Neurol. · Pubmed #12666096 No free full text.

Abstract: Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.

Jenner P. · Neurodegenerative Disease Research Centre, Hodgkin Building, GKT School of Biomedical Sciences, King's College, SE1 1UL, London, UK. · Parkinsonism Relat Disord. · Pubmed #12573867 No free full text.

Abstract: 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.

Jenner P. · Neurodegenerative Diseases Research Centre, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, UK. · Neurology. · Pubmed #11909980 No free full text.

Abstract: There is now increasing use of dopamine agonists as effective early monotherapy in the treatment of Parkinson's disease (PD). Dopamine agonists can induce an antiparkinsonian effect through actions on either D(1)-like or D(2)-like dopamine receptors, and the multiple receptor subtypes present in the brain may provide further opportunities to improve the treatment of PD. Functional interactions exist between D(1)- and D(2)-like receptors, and adaptive changes occur after denervation and repeated administration of a dopamine agonist. Long-acting dopamine agonists produce a lower incidence of dyskinesia than levodopa (L-dopa) when they are used as monotherapy in either PD or in drug-naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Continuous dopaminergic stimulation appears less likely to prime basal ganglia for involuntary movements compared with drugs, such as L-dopa, that produce pulsatile stimulation. However, once priming has occurred, dopamine agonists produce dyskinesia identical to that of L-dopa. Continuous administration of long-acting dopamine agonists may reverse the priming process initiated by L-dopa, markedly decreasing dyskinesia intensity with a minimal loss of antiparkinsonian activity, at least in MPTP-treated primates. Dopamine receptors in brain areas other than the striatum, such as the globus pallidus and subthalamic nucleus, and in the mesolimbic and mesocortical regions may also contribute to antiparkinsonian activity of dopamine agonists and their associated side effects. The future potential of dopamine agonists may lie in the selective stimulation of dopamine receptor subtypes in different brain areas and through the actions of partial dopamine agonists and drugs that normalize dopamine receptor function.

McNaught KS, Lee M, Hyun DH, Jenner P. · Neurodegenerative Disease Research Centre, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, U.K. · Adv Neurol. · Pubmed #11554011 No free full text.

This publication has no abstract.

McNaught KS, Olanow CW, Halliwell B, Isacson O, Jenner P. · Neuroregeneration Laboratory, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. · Nat Rev Neurosci. · Pubmed #11484002 No free full text.

This publication has no abstract.

Jenner P. · King's College London, Manresa Road, London, UK SW3 6LX. · Trends Neurosci. · Pubmed #11311359 No free full text.

Abstract: Selective nigral degeneration with inclusion formation provoked by systemic administration of the herbicide rotenone, through inhibition of complex I, raises the question of pesticide exposure and environmental factors in general, as a cause of Parkinson's disease (PD). Toxin-induced complex I inhibition probably represents one of many potential causes of PD, but it alerts us to the dangers of such substances in the environment and the need to identify genetically susceptible populations. When vulnerable individuals become known, perhaps they should stay out of the garden.

Jenner P. · Neurodegenerative Process Research Center, Guy's King's and St Thomas' School of Biomedical Sciences, King's College London, UK. · J Neurol. · Pubmed #10991665 No free full text.

Abstract: Levodopa-induced dyskinesia is a major therapeutic problem in the long-term treatment of Parkinson's disease. The development of dyskinesia is dependent on the extent of nigral denervation but can be induced through both D-1 and D-2 dopamine receptors. Short-acting dopamine agonists producing pulsatile receptor stimulation are more likely to induce dyskinesia than long-acting drugs that produce continuous receptor stimulation. However, there are no consistent changes in dopamine receptors which explain the occurrence of dyskinesia. Rather, dyskinesia may originate from an imbalance between the major striatal output pathways. Indeed, levodopa and dopamine agonist drugs show a differential ability to alter striatal output as judged by mRNA for colocalised neuropeptides. The involvement of striatal output pathways raises the possibility of utilising a range of non-dopaminergic receptors within the striatum and in output nuclei as targets for novel drug therapies which may be antiparkinsonian without eliciting dyskinesia. For example, the A2a adenosine antagonist KW6002 reverses motor deficits in primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) without provoking an established dyskinesia. Similarly, manipulation of muscarinic cholinergic receptors in the striatum can alter the intensity and components of dyskinesia. Neurotrophic therapies diminish dyskinesia since glial cell line-derived neurotrophic factor (GDNF) produces a decrease in motor disability in MPTP-treated primates associated with a reduced intensity of levodopa-induced dyskinesia. The mechanisms underlying the manifestations and the priming process for dyskinesia remain unknown, but non-dopaminergic approaches to therapy may provide an effective way of preventing, or limiting, the expression of involuntary movements in Parkinson's disease.

Riedl AG, Watts PM, Brown CT, Jenner P. · Neurodegenerative Disease Research Centre, King's College, London, United Kingdom. · Adv Neurol. · Pubmed #10410732 No free full text.

This publication has no abstract.

Rose S, MacKenzie GM, Jenner P. · Neurodegenerative Diseases Research Centre, King's College, London, United Kingdom. · Adv Neurol. · Pubmed #10410729 No free full text.

This publication has no abstract.

Iczkiewicz J, Jackson MJ, Smith LA, Rose S, Jenner P. · Neurodegenerative Diseases Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London, UK. · Brain Res. · Pubmed #16962083 No free full text.

Abstract: Parkinson's disease (PD) is characterised by the loss of dopaminergic neurones in the substantia nigra (SN) but the pathogenic mechanism remains unknown. Cell death involves oxidative stress and inflammatory mechanisms, and these may be altered by the actions of the glycosylated phosphoprotein osteopontin (OPN). OPN is present in the rat SN, but its presence in human and non-human primate brain has not been extensively studied. Both OPN mRNA and protein were present in the normal marmoset SN, and OPN protein was localised to nigral neurones although these were not dopaminergic cells and it was not present in glial cells. In contrast, OPN protein was found in dopaminergic neurones in the normal human SN but again not in glial cells with some accumulation in the extracellular matrix. Following MPTP treatment of common marmosets, OPN protein expression was decreased, although its mRNA levels were unchanged and it was not present in either activated microglia or astrocytes. In the SN in PD, OPN protein expression was decreased in the remaining dopaminergic neurones and it was present in activated microglia but not in astrocytes. This was not specific to PD as OPN protein expression was also decreased in the SN in multiple system atrophy and progressive supranuclear palsy with an identical localisation of the protein. The presence of OPN in the normal human and non-human primate SN coupled to its decreased expression following nigral cell degeneration suggests that it may play an important role in dopaminergic neurone survival.