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Novel Pharmacological Targets for the Treatment of Parkinson's Disease

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Novel Pharmacological Targets for the Treatment of Parkinson's Disease REVIEWS Novel pharmacological targets for the treatment of Parkinson’s disease Anthony H. V. Schapira*,‡, Erwan Bezard§, Jonathan Brotchie||, Frédéric Calon¶, Graham L. Collingridge#, Borris Ferger**, Bastian Hengerer**, Etienne Hirsch‡‡,§§, Peter Jenner||||, Nicolas Le Novère¶¶, José A. Obeso##, Michael A. Schwarzschild***, Umberto Spampinato‡‡‡ and Giora Davidai§§§ 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. Bradykinesia Parkinson’s disease (PD) is a multicentric neurodegen- those aimed at managing or preventing the onset of motor Abnormally slow voluntary erative disease with a prevalence of approximately 1 in complications), the identification of non-dopaminergic movements. 300. Clinical features at presentation include the asym- drugs for symptomatic improvement and the discovery metric onset of bradykinesia, rigidity and tremor. These of compounds to modify the course of PD. Lewy body Abnormal aggregates of are the result of the loss of dopaminergic neurons in the protein (predominately substantia nigra pars compacta, which causes a con- Dopaminergic drugs α-synuclein) that develop sequent reduction of dopamine levels in the striatum Dopamine-replacement therapy has dominated the treat- inside nerve cells and displace (FIG. 1). However, additional neuronal fields and neuro- ment of motor symptoms of PD since the early 1960s. The other cell components. transmitter systems are also involved in PD, including effects are predictable (as are the side effects) and none of Dyskinesia the locus coeruleus, dorsal motor nucleus, substantia the more recently introduced synthetic dopamine agonists Involuntary writhing innominata, the autonomic nervous system and the has surpassed the clinical benefit derived from levodopa movements affecting head, cerebral cortex (FIG.2). Consequently non-adrenergic, (!-DOPA)2,3 (TABLE 1). Most recently, non-oral delivery has trunk and limbs. serotinergic and cholinergic neurons are also lost. provided more long-lasting anti-Parkinsonian activity This loss results in symptoms that include cognitive through the subcutaneous or intravenous infusion of decline, sleep abnormalities and depression, as well as apomorphine and transdermal patch technology with gastrointestinal and genitourinary disturbances. These rotigotine or lisuride4,5. However, despite the many *University Department of ‘non-motor’ features progress and come to dominate dopaminergic agents currently available, the search for Clinical Neurosciences, Royal the later stages of PD. Although the clinical conse- novel approaches based on dopamine-replacement therapy Free and University College quences of non-dopaminergic neuronal involvement continues. The multiplicity of dopamine receptors in Medical School, University usually become apparent some years after diagnosis, the brain offers a range of potential targets, but so far College London, Rowland Hill Street, London NW3 2PF, UK. there is debate about the sequence in which PD pathol- exploitation of drugs acting on specific receptor subtypes ‡Institute of Neurology, ogy develops. The distribution of Lewy body formation has been disappointing. Most currently used drugs only 6 Queen Square, University might include non-dopaminergic areas at an early activate D2 and D3 dopamine receptors and no major College London, London 1 stage ; however, it remains to be shown that cell death advance has been made in producing D1 dopamine ago- WC1N 3BG, UK. occurs in these areas before the substantia nigra. nists, a known target for anti-Parkinsonian agents. Partial Correspondence to A.H.V.S.: e-mail:a.schapira@medsch. The three main strategic developments that have led to D2 dopamine agonists are being developed as they might ucl.ac.uk progress in the medical management of PD have focussed treat the motor symptoms of Parkinson’s disease while doi:10.1038/nrd2087 on improvements in dopaminergic therapies, (including suppressing both psychosis and dyskinesia7. NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 845 REVIEWS Author addresses Anticholinergics were among the first drugs used in PD, and were intended to correct the imbalance § CNRS UMR 5543, Universite Victor Segalen–Bordeaux 2, 146, rue Leo Saignat, 33076 between dopamine and acetylcholine levels. Although Bordeaux cedex, France. these drugs do produce some beneficial effects on PD ||Toronto Western Research Institute, Toronto Western Hospital, 399 Bathurst, MC symptoms, they are associated with adverse cogni- 11-419, Toronto, Ontario M5T 2S8, Canada. 17 ¶Molecular Endocrinology and Oncology Research Centre, Centre Hospitalier de tive effects . Many cholinesterase inhibitors, such l’Université Laval Research Centre (CHUL), Quebec (QC), Canada, G1V 4G2 and Faculty as rivastigmine (Exelon; Novartis) and donepezil of Pharmacy, Laval University, Quebec G1K 7P4, Canada. (Aricept; Eisai/Pfizer), have been tested to counter- #MRC Centre for Synaptic Plasticity, University of Bristol, University Walk, Bristol, act PD dementia, and have been found to improve BS8 1TD, UK. cognition18–21. However, they sometimes display **Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany. mixed effects on motor function22. It might be that ‡‡INSERM, UMR 679, Neurology and Experimental Therapeutics, Paris, France. co-treatment using a combination of anticholinergics §§ University Pierre et Marie Curie, Hôpital de la Pitié-Salpétrière, Paris, France. and anticholinesterases would correct acetylcholine |||| Neurodegenerative Disease Research Centre, School of Health and Biomedical deficits while counteracting the hypersensitivity of Sciences, King’ s College, London SE1 1UL, UK. cortical muscarinic receptors. ¶¶Computational Neurobiology, EMBL-EBI. Wellcome-Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Nicotinic receptors are not only highly expressed 23 ##Department of Neurology and Neuroscience Centre, Clinica Universitaria and Medical on dopaminergic neurons , but also in the cortex and School, Universidad de Navarra and CIMA, Avenida de Pio XII, Pamplona 31008, Spain. thalamus. Nicotine has been found to protect against ***Department of Neurology, Massachusetts General Hospital, MassGeneral Institute degeneration in various PD models24,25. In addition, an for Neurodegenerative Disease, 114 16th Street, Boston, Massachusetts 02129, USA. inverse association between smoking and PD has been ‡‡‡14 Unité Mixte de Recherche-Centre National de la Recherche Scientifique, consistently demonstrated26. However, nicotine itself (UMR-CNRS) 5541, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignât, B.P. 31, has no anti-Parkinsonian effect and the mechanism by 33076 Bordeaux Cedex, France. which smoking might confer protection against PD is §§§ Department of Cardiovascular Medicine and Neurology, Clinical and Scientific Affairs, not known. Boehringer Ingelheim, 900 Ridgeway Road, Ridgefield, Connecticut CT06877, USA. Serotoninergic drugs 5-HT receptors are crucial to motor control in health 27–33 Although !-DOPA is the most effective drug for the and disease . In PD, 5-HT1A, 5-HT1B, 5-HT2A and control of motor symptoms, it also causes a high level 5-HT2C deserve special attention, particularly with of motor complications, particularly dyskinesias8. By respect to involvement in !-DOPA -induced dyskinesia contrast, dopamine agonists produce a lower incidence (LID). of involuntary movements, which seems to reflect their In monkeys given 1-methyl-4-phenyl-1,2,3,6-tet- longer duration of action and supports the concept of rahydropyridine (MPTP), which induces Parkinsonian 9,10 continuous dopaminergic stimulation . This has been symptoms, the 5HT1A receptor agonists sarizotan exploited by the introduction of a range of long-acting (Merck)34 and 8-hydroxy-2-di-n-propylamino-tetralin dopamine agonists, by the use of !-DOPA in combina- (8-OH-DPAT)35 dramatically reduce LID. In clinical 11 tion with catechol-O-methyl transferase inhibitors and trials, sarizotan and another 5HT1A agonist, buspirone, more recently by development of once-daily controlled- reduced LID36–38 and extended the duration of !-DOPA released formulations of dopamine agonist drugs and the action37. However, at high doses, sarizotan can exacer- introduction of transdermal dopamine agonist delivery7. bate Parkinsonism36. This might reflect an interaction Whether continuous dopaminergic stimulation explains with D2 dopamine receptors. Therefore in developing all of the differences between !-DOPA and dopamine the next generation of 5-HT1A agonists, it might be agonists is a matter of contention. There might instead be beneficial to remove D2 activity. The potential value of fundamental differences between the actions of !-DOPA developing such compounds is highlighted by recent and those of dopamine agonists. Unlike
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