Adenosin A_2A Rezeptorantagonisten als Therapieoption beim idiopathischen Parkinson-Syndrom?

Zusammenfassung

Beim Parkinson-Syndrom wurde sich lange Zeit auf die motorischen Symptome und die Therapie mit dopaminergen Substanzen fokussiert. In den letzten Jahren gewannen die nicht-motorischen Symptome immer mehr Bedeutung, da sie früh im Krankheitsverlauf auftreten und die Lebensqualität erheblich einschränken. Dadurch wurde aber auch die Notwendigkeit einer Behandlung nicht nur des dopaminergen Defizits offensichtlich. Als weitere therapeutische Option wurden die Adenosin A_2A Rezeptorantagonisten entwickelt, da Adenosin A_2A Rezeptorantagonisten nicht-dopaminerg und selektiv in den Basalganglien lokalisiert sind. Somit besteht die Möglichkeit striato-thalamo-kortikalen Schleifen zusätzlich zu modulieren. Bereits 2013 wurde ein Adenosin A_2A Rezeptorantagonist in Japan und in 2019 in den USA als Add-on zu L-DOPA zugelassen. Mit einer Zulassung in Europa wird in naher Zukunft gerechnet. In dieser Übersicht möchten wir die theoretischen Grundlagen dieses Therapieansatzes darstellen und die aktuellen Daten zur Wirksamkeit und dem therapeutischen Einsatz referieren.

Abstract

In Parkinson’s disease, the focus has long been on motor symptoms and therapy with dopaminergic substances. In recent years, the importance of non-motor symptoms has been increasingly recognized, as they occur early in the course of the disease and restrict considerably the quality of life. However, this also made the need for treatment of non-dopaminergic deficits obvious. Adenosine A_2A receptor antagonists were identified as an additional therapy, since the adenosine A_2A receptors are non-dopaminergic and selectively localized in the basal ganglia. This means that the striato-thalamo-cortical loops can be modulated. An adenosine A_2A receptor antagonist was already approved in Japan in 2013 and in the USA in 2019 as an add-on to L-DOPA. Approval for this drug in Europe is expected in the near future. In this overview, we present the theoretical basis and current data on its efficacy and therapeutic use.

Schlüsselwörter

idiopathisches Parkinson-Syndrom - nicht-motorische Symptome - Adenosin A_2A Rezeptorantagonisten

Key words

Parkinson’s disease - non-motor symptoms - adenosine A_2A receptor antagonists

• Literatur

• 1 Kanda T, Jenner P. Can adenosine A2A receptor antagonists modify motor behavior and dyskinesia in experimental models of Parkinson’s disease? Parkinsonism Relat Disord. 2020; 80: S21-S27
• 2 LeWitt PA, Chaudhuri KR. Unmet needs in Parkinson disease: Motor and non-motor. Parkinsonism Relat Disord. 2020; 80: S7-S12
• 3 Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM. et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord 2011; 26: 399-406
• 4 Valkovic P, Harsany J, Hanakova M. et al. Nonmotor symptoms in early- and advanced-stage Parkinson’s disease patients on dopaminergic therapy: how do they correlate with quality of life?. ISRN Neurol 2014; 2014: 587302
• 5 Uebelacker LA, Epstein-Lubow G, Lewis T. et al. A survey of Parkinson’s disease patients: most bothersome symptoms and coping preferences. J Parkinsons Dis 2014; 4: 717-723
• 6 LeWitt PA, Jenner P. Introduction. Parkinsonism Relat Disord 2020; 80: S1-S2
• 7 Solinas M, Ferre S, You ZB. et al. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 2002; 22: 6321-6324
• 8 Olopade F, Femi-Akinlosotu O, Adekanmbi A. et al. Chronic Caffeine Ingestion Improves Motor Function and Increases Dendritic Length and Arborization in the Motor Cortex, Striatum, and Cerebellum. Journal of Caffeine and Adenosine Research 2021; 11: 3-14
• 9 Sheth S, Brito R, Mukherjea D. et al. Adenosine receptors: expression, function and regulation. Int J Mol Sci 2014; 15: 2024-2052
• 10 Liu YJ, Chen J, Li X. et al. Research progress on adenosine in central nervous system diseases. CNS Neurosci Ther 2019; 25: 899-910
• 11 Jenner P, Mori A, Kanda T. Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson’s disease?. Parkinsonism Relat Disord 2020; 80: S28-S36
• 12 Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13: 266-271
• 13 Mori A. How do adenosine A2A receptors regulate motor function?. Parkinsonism Relat Disord 2020; 80: S13-S20
• 14 Gonzalez-Latapi P, Bhowmick SS, Saranza G. et al. Non-Dopaminergic Treatments for Motor Control in Parkinson’s Disease: An Update. CNS Drugs 2020; 34: 1025-1044
• 15 LeWitt PA, Aradi SD, Hauser RA. et al. The challenge of developing adenosine A2A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant. Parkinsonism Relat Disord 2020; 80: S54-S63
• 16 Uchida S, Soshiroda K, Okita E. et al. The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets. Eur J Pharmacol 2015; 747: 160-165
• 17 Uchida S, Soshiroda K, Okita E. et al. The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets. Eur J Pharmacol 2015; 766: 25-30
• 18 Uchida S, Tashiro T, Kawai-Uchida M. et al. Adenosine A₂A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci 2014; 124: 480-485
• 19 Bakshi R, Macklin EA, Hung AY. et al. Associations of Lower Caffeine Intake and Plasma Urate Levels with Idiopathic Parkinson’s Disease in the Harvard Biomarkers Study. J Parkinsons Dis 2020; 10: 505-510
• 20 Fujimaki M, Saiki S, Li Y. et al. Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. Neurology 2018; 90: e404-e411
• 21 Crotty GF, Maciuca R, Macklin EA. et al. Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study. Neurology 2020; 95: e3428-e3437
• 22 Ohmichi T, Kasai T, Kosaka T. et al. Biomarker repurposing: Therapeutic drug monitoring of serum theophylline offers a potential diagnostic biomarker of Parkinson’s disease. PLoS One 2018; 13: e0201260
• 23 Hong CT, Chan L, Bai CH. The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis. Nutrients 2020; 12
• 24 Maclagan LC, Visanji NP, Cheng Y. et al. Identifying drugs with disease-modifying potential in Parkinson’s disease using artificial intelligence and pharmacoepidemiology. Pharmacoepidemiol Drug Saf 2020; 29: 864-872
• 25 Sako W, Murakami N, Motohama K. et al. The effect of istradefylline for Parkinson’s disease: A meta-analysis. Sci Rep 2017; 7: 18018
• 26 Nagayama H, Kano O, Murakami H. et al. Effect of istradefylline on mood disorders in Parkinson’s disease. J Neurol Sci 2019; 396: 78-83
• 27 Bara-Jimenez W, Sherzai A, Dimitrova T. et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology 2003; 61: 293-296
• 28 Factor S, Mark MH, Watts R. et al. A long-term study of istradefylline in subjects with fluctuating Parkinson’s disease. Parkinsonism Relat Disord 2010; 16: 423-426
• 29 Fernandez HH, Greeley DR, Zweig RM. et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord 2010; 16: 16-20
• 30 Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 2003; 61: 297-303
• 31 Hauser RA, Shulman LM, Trugman JM. et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008; 23: 2177-2185
• 32 LeWitt PA, Guttman M, Tetrud JW. et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 2008; 63: 295-302
• 33 Mizuno Y, Hasegawa K, Kondo T. et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord 2010; 25: 1437-1443
• 34 Mizuno Y, Kondo T. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord 2013; 28: 1138-1141
• 35 Pourcher E, Fernandez HH, Stacy M. et al. Istradefylline for Parkinson’s disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 2012; 18: 178-184
• 36 Stacy M, Silver D, Mendis T. et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 2008; 70: 2233-2240
• 37 Michel A, Nicolas JM, Rose S. et al. Antiparkinsonian effects of the “Radiprodil and Tozadenant” combination in MPTP-treated marmosets. PLoS One 2017; 12: e0182887
• 38 Hauser RA, Stocchi F, Rascol O. et al. Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned. JAMA Neurology 2015; 72: 1491-1500
• 39 Cutler DL, Tendolkar A, Grachev ID. Safety, tolerability and pharmacokinetics after single and multiple doses of preladenant (SCH420814) administered in healthy subjects. J Clin Pharm Ther 2012; 37: 578-587
• 40 Factor SA, Wolski K, Togasaki DM. et al. Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson’s disease. Mov Disord 2013; 28: 817-820
• 41 Hattori N, Kikuchi M, Adachi N. et al. Adjunctive preladenant: A placebo-controlled, dose-finding study in Japanese patients with Parkinson’s disease. Parkinsonism Relat Disord 2016; 32: 73-79
• 42 Hauser RA, Cantillon M, Pourcher E. et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 2011; 10: 221-229
• 43 Hauser RA, Stocchi F, Rascol O. et al. Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned. JAMA Neurol 2015; 72: 1491-1500
• 44 Stocchi F, Rascol O, Hauser RA. et al. Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology 2017; 88: 2198-2206
• 45 Hauser RA, Olanow CW, Kieburtz KD. et al. Tozadenant (SYN115) in patients with Parkinson’s disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol 2014; 13: 767-776
• 46 Isaacson S, Eggert K, Kumar R. et al. Efficacy and safety of istradefylline in moderate to severe Parkinson’s disease: A phase 3, multinational, randomized, double-blind, placebo-controlled trial (i-step study). Journal of the Neurological Sciences 2017; 381: 351-352
• 47 https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-000817-20/results. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-000817-20/results
• 48 Mizuno Y, Hasegawa K, Kondo T. et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: A randomized, controlled study. Movement Disorders 2010; 25: 1437-1443
• 49 Kondo T, Mizuno Y. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol 2015; 38: 41-46
• 50 Takahashi M, Fujita M, Asai N. et al. Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan. Expert Opin Pharmacother 2018; 19: 1635-1642
• 51 Yamada K, Kobayashi M, Shiozaki S. et al. Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. Psychopharmacology (Berl) 2014; 231: 2839-2849
• 52 Yamada K, Kobayashi M, Mori A. et al. Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents. Pharmacol Biochem Behav 2013; 114-115: 23-30
• 53 Minor TR, Hanff TC. Adenosine signaling in reserpine-induced depression in rats. Behav Brain Res 2015; 286: 184-191
• 54 El Yacoubi M, Ledent C, Parmentier M. et al. Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice. British journal of pharmacology 2001; 134: 68-77
• 55 Porkka-Heiskanen T, Strecker RE, Thakkar M. et al. Adenosine: A Mediator of the Sleep-Inducing Effects of Prolonged Wakefulness. Science 1997; 276: 1265-1268
• 56 Urade Y, Eguchi N, Qu W-M. et al. Minireview: Sleep regulation in adenosine A2A receptor-deficient mice. Neurology 2003; 61: S94-S96
• 57 Huang Z-L, Qu W-M, Eguchi N. et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nature Neuroscience 2005; 8: 858-859
• 58 Suzuki K, Miyamoto M, Miyamoto T. et al. Istradefylline improves daytime sleepiness in patients with Parkinson’s disease: An open-label, 3-month study. J Neurol Sci 2017; 380: 230-233
• 59 Matsuura K, Kajikawa H, Tabei KI. et al. The effectiveness of istradefylline for the treatment of gait deficits and sleepiness in patients with Parkinson’s disease. Neurosci Lett 2018; 662: 158-161
• 60 Sonsalla PK, Wong LY, Harris SL. et al. Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson’s disease. Exp Neurol 2012; 234: 482-487
• 61 Rozan P, Hidalgo S, Nejdi A. et al. Preventive antioxidant effects of cocoa polyphenolic extract on free radical production and cognitive performances after heat exposure in Wistar rats. J Food Sci 2007; 72: S203-S206
• 62 Chen JF, Xu K, Petzer JP. et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci 2001; 21: Rc143
• 63 Khadrawy YA, Salem AM, El-Shamy KA. et al. Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson’s Disease Induced by Rotenone. Journal of Dietary Supplements 2017; 14: 553-572
• 64 Luan Y, Ren X, Zheng W. et al. Chronic Caffeine Treatment Protects Against alpha-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum. Front Neurosci 2018; 12: 301
• 65 Chen JF, Schwarzschild MA. Do caffeine and more selective adenosine A2A receptor antagonists protect against dopaminergic neurodegeneration in Parkinson’s disease? Parkinsonism Relat Disord. 2020; 80: S45-S53