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Emerging Therapies for Parkinson's Disease: from Bench to Bedside

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Emerging Therapies for Parkinson's Disease: from Bench to Bedside JPT-06691; No of Pages 11 Pharmacology & Therapeutics xxx (2014) xxx–xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera 1 Emerging therapies for Parkinson's disease: From bench to bedside 2Q1 F.I. Tarazi a,⁎,Z.Sahlia,c, M. Wolny b,S.A.Mousab 3 a Department of Psychiatry and Neuroscience Program, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA 4 b The Pharmaceutical Research Institute at Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA 5 c School of Medicine, American University of Beirut, Beirut, Lebanon 6 article info abstract 7 8Q2 Keywords: The prevalence of Parkinson's disease (PD) increases with age and is projected to increase in parallel to the rising 18 9 Adenosine A2A antagonists average age of the population. The disease can have significant health-related, social, and financial implications 19 10 Anti-apoptotic agents not only for the patient and the caregiver, but for the health care system as well. While the neuropathology of 20 11 Antioxidants this neurodegenerative disorder is fairly well understood, its etiology remains a mystery, making it difficult to 21 12 Deep brain stimulation target therapy. The currently available drugs for treatment provide only symptomatic relief and do not control 22 13 MicroRNAs or prevent disease progression, and as a result patient compliance and satisfaction are low. Several emerging 23 14 Parkinson's disease pharmacotherapies for PD are in different stages of clinical development. These therapies include adenosine 24 15 Pallidotomy 25 16 Stem cells A2A receptor antagonists, glutamate receptor antagonists, monoamine oxidase inhibitors, anti-apoptotic agents, 17 Viral vector gene therapy and antioxidants such as coenzyme Q10, N-acetyl cysteine, and edaravone. Other emerging non- 26 pharmacotherapies include viral vector gene therapy, microRNAs, transglutaminases, RTP801, stem cells and 27 glial derived neurotrophic factor (GDNF). In addition, surgical procedures including deep brain stimulation, pal- 28 lidotomy, thalamotomy and gamma knife surgery have emerged as alternative interventions for advanced PD pa- 29 tients who have completely utilized standard treatments and still suffer from persistent motor fluctuations. 30 While several of these therapies hold much promise in delaying the onset of the disease and slowing its progres- 31 sion, more pharmacotherapies and surgical interventions need to be investigated in different stages of PD. It is 32 hoped that these emerging therapies and surgical procedures will strengthen our clinical armamentarium for im- 33 proved treatment of PD. 34 35 © 2014 Published by Elsevier Inc. 363739 38 4041 Contents 42 1. Introduction............................................... 0 43 2. Emergingpharmacotherapies........................................ 0 44 3. Emergingnon-pharmacotherapies..................................... 0 45 4. Emergingsurgicalprocedures....................................... 0 46 5. Conclusions................................................ 0 47 Conflictofinterest............................................... 0 48 References................................................... 0 49 50 1. Introduction 65 years old. It is estimated that the number of Parkinson's disease pa- 55 UNCORRECTEDtients will increase PROOF from 4.1 million in 2005 to 8.7 million in 2030. 56 51 Parkinson's disease (PD) is the second most common neurodegener- The lifetime risk for PD in men is 2.0%, while in women it is 1.3%. 57 52 ative disorder that currently affects over 1 million Americans with There are also cases known as early-onset PD where the disease mani- 58 53 about 40,000–50,000 new cases diagnosed every year. The prevalence fests in individuals around the age of 45, but these only comprise a 59 54 of PD increases with age, with the normal age of onset being around small portion of the PD population (Tanner et al., 1997; McNaught & 60 Olanow, 2006; Rao et al., 2006). 61 PD typically presents in a sporadic idiopathic fashion (Cookson & 62 ⁎ Corresponding author at: Harvard Medical School and McLean Hospital, 115 Mill 63 Street, Belmont, MA 02478, USA. Tel.: 617 855 3176; fax: 617 855 3479. Bandmann, 2010). Hereditary factors play a minimal role because only E-mail address: [email protected] (F.I. Tarazi). 10% of all PD cases are found to have genetic links involved, and these 64 http://dx.doi.org/10.1016/j.pharmthera.2014.05.010 0163-7258/© 2014 Published by Elsevier Inc. Please cite this article as: Tarazi, F.I., et al., Emerging therapies for Parkinson's disease: From bench to bedside, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.05.010 2 F.I. Tarazi et al. / Pharmacology & Therapeutics xxx (2014) xxx–xxx 65 are most closely associated with early-onset PD (Bekris et al., 2010). For breakdown by MAO into DOPAC. In the prefrontal cortex, where 127 66 example, autosomal recessive inheritance linked to the PARKIN gene has dopamine innervations are lower than in striatum, dopamine is 128 67 been reported in a large number of early-onset cases (Polymeropoulos inactivated by reuptake via the norepinephrine transporter and enzy- 129 68 et al., 1997; Kitada et al., 1998). Other suspected causes include environ- matic breakdown by COMT into 3-MT (Elsworth & Roth, 1997; Kandel 130 69 mental toxins, medications, and viruses that all result in an increase in et al., 2000). 131 70 oxidative stress (Di Monte et al., 2002; Jenner & Olanow, 2006). Oxida- Pharmacotherapies that are currently used for treatment of PD focus 132 71 tive stress leads to generation of free radicals, which induces apoptotic only on the symptomatic component of the disease by attempting to re- 133 72 cell death in dopamine neurons, particularly those neurons projecting plenish the dopamine content in the brain, but these therapies do not 134 73 from the substantia nigra pars compacta to the caudate-putamen prevent the progression of the disease. L-DOPA remains as the gold stan- 135 74 (Baldessarini & Tarazi, 1996; Naoi & Maruyama, 1999). Some of the do- dard because it can readily cross the blood brain barrier (BBB) and is 136 75 paminergic neurons that survive contain Lewy bodies, which consist of converted to dopamine by the actions of the enzyme DOPA decarboxyl- 137 76 aggregates of proteins thought to cause neurodegeneration (McNaught, ase (Hornykiewicz, 2002). Because L-DOPA is also converted into dopa- 138 77 2004; Olanow & McNaught, 2006). However, it remains to be deter- mine in the peripheral nervous system, causing undesirable adverse 139 78 mined if the Lewy bodies cause the neurodegeneration of dopamine events such as nausea and vomiting, it is standard in clinical practice 140 79 neurons or result from such a process. to co-administer L-DOPA with DOPA decarboxylase inhibitor such as 141 carbidopa that does not cross the blood–brain barrier. This inhibition 142 80 1.1. Clinical symptoms and diagnosis can reduce conversion of L-DOPA to dopamine in the peripheral tissue 143 and therefore increase L-DOPA delivery to the brain (Nagatsua & 144 81 PD symptoms vary among patients and may include tremor [e.g. Sawadab, 2009). A controlled release formulation of levodopa/ 145 82 hand tremor at rest], loss of spontaneous movements, facial expression carbidopa [Sinemet CR®] is also available to provide more sustained 146 83 and eye blinking [akinesia and bradykinesia], muscle rigidity, impaired levodopa plasma levels than standard levodopa/carbidopa [Sinemet®] 147 84 posture and balance, and changes in speech fluency [reduced volume (Rodnitzky, 1992). Nonetheless, long-term levodopa treatment is asso- 148 85 and clarity] and handwriting [less legible] (Tolosa et al., 2006; ciated with significant complications including involuntary movements, 149 86 Jankovic, 2008; Pahwa & Lyons, 2010). Patients are typically diagnosed dyskinesias, and response fluctuations “wearing off” effect (Jankovic, 150 87 based on their medical history and an extensive neurological and 2005). Another levodopa formulation that combines levodopa/ 151 88 physical examination. The diagnosis is likely when two out of the four carbidopa with the COMT inhibitor entacapone in a single tablet 152 89 cardinal symptoms of PD [tremor, rigidity, akinesia, and postural insta- [Stalevo®] is also available for treatment of PD patients (Silver, 2004). 153 90 bility] are present (Hermanowicz, 2001). Brain scans are used to rule COMT inhibitors are not effective independently, but they prolong the 154 91 out related disorders like progressive supranuclear palsy, drug- availability of levodopa to the brain and are clinically beneficial as 155 92 induced parkinsonism, vascular parkinsonism, and diffuse Lewy body adjunctive treatment to levodopa therapy in PD patients with end-of- 156 93 disease (Piccini & Whone, 2004; Piccini & Brooks, 2006). Non-motor dose fluctuations (Ruottinen & Rinne, 1998). Other valid pharmacother- 157 94 symptoms including memory impairment, executive deficits, sleep apies include dopamine agonists, which typically target dopamine post- 158 95 disturbances, depression, hallucinations as well as autonomic nervous synaptic D2 receptors. Among these agents are the ergot derivatives 159 96 system dysfunction resulting in constipation, urinary frequency and bromocriptine [Parlodel®], lisuride [Dopergin®], pergolide [Permax®], 160 97 incontinence, and orthostatic hypotension are also common, and can and cabergoline [Dostinex®], as well as other agents that
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