The Pharmacological Potential of Adenosine A Receptor Antagonists for Treating Parkinson's Disease

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Apr 12

PMID 35408767

Authors

Akihisa Mori

Jiang-Fan Chen

Shinichi Uchida

Cecile Durlach

Shelby M King

Peter Jenner

Affiliations

Soon will be listed here.

Abstract

The adenosine A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson's disease (PD). The selective A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.

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References

Hino T, Arakawa T, Iwanari H, Yurugi-Kobayashi T, Ikeda-Suno C, Nakada-Nakura Y . G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature. 2012; 482(7384):237-40. PMC: 3303121. DOI: 10.1038/nature10750. View

Muller T, Mueller B, Riederer P . Perspective: Treatment for Disease Modification in Chronic Neurodegeneration. Cells. 2021; 10(4). PMC: 8069143. DOI: 10.3390/cells10040873. View

Rebola N, Rodrigues R, Lopes L, Richardson P, Oliveira C, Cunha R . Adenosine A1 and A2A receptors are co-expressed in pyramidal neurons and co-localized in glutamatergic nerve terminals of the rat hippocampus. Neuroscience. 2005; 133(1):79-83. DOI: 10.1016/j.neuroscience.2005.01.054. View

Gerfen C, Engber T, Mahan L, Susel Z, Chase T, Monsma Jr F . D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science. 1990; 250(4986):1429-32. DOI: 10.1126/science.2147780. View

Mori A . How do adenosine A receptors regulate motor function?. Parkinsonism Relat Disord. 2020; 80 Suppl 1:S13-S20. DOI: 10.1016/j.parkreldis.2020.09.025. View

Huang Z, Qu W, Eguchi N, Chen J, Schwarzschild M, Fredholm B . Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci. 2005; 8(7):858-9. DOI: 10.1038/nn1491. View

Shindou T, Mori A, Kase H, Ichimura M . Adenosine A(2A) receptor enhances GABA(A)-mediated IPSCs in the rat globus pallidus. J Physiol. 2001; 532(Pt 2):423-34. PMC: 2278560. DOI: 10.1111/j.1469-7793.2001.0423f.x. View

Santangelo G, Vitale C, Picillo M, Cuoco S, Moccia M, Pezzella D . Apathy and striatal dopamine transporter levels in de-novo, untreated Parkinson's disease patients. Parkinsonism Relat Disord. 2015; 21(5):489-93. DOI: 10.1016/j.parkreldis.2015.02.015. View

Chen J, Xu K, Petzer J, Staal R, Xu Y, Beilstein M . Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci. 2001; 21(10):RC143. PMC: 6762498. View

10.

Viana da Silva S, Haberl M, Zhang P, Bethge P, Lemos C, Goncalves N . Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors. Nat Commun. 2016; 7:11915. PMC: 4915032. DOI: 10.1038/ncomms11915. View

11.

Mori A, Shindou T . Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists. Neurology. 2003; 61(11 Suppl 6):S44-8. DOI: 10.1212/01.wnl.0000095211.71092.a0. View

12.

Svenningsson P, Hall H, Sedvall G, Fredholm B . Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse. 1998; 27(4):322-35. DOI: 10.1002/(SICI)1098-2396(199712)27:4<322::AID-SYN6>3.0.CO;2-E. View

13.

Xu K, Xu Y, Chen J, Schwarzschild M . Caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice. Neurosci Lett. 2002; 322(1):13-6. DOI: 10.1016/s0304-3940(02)00069-1. View

14.

Weintraub D, Aarsland D, Chaudhuri K, Dobkin R, Leentjens A, Rodriguez-Violante M . The neuropsychiatry of Parkinson's disease: advances and challenges. Lancet Neurol. 2021; 21(1):89-102. PMC: 8800169. DOI: 10.1016/S1474-4422(21)00330-6. View

15.

Ishiwata K, Ogi N, Hayakawa N, Oda K, Nagaoka T, Toyama H . Adenosine A2A receptor imaging with [11C]KF18446 PET in the rat brain after quinolinic acid lesion: comparison with the dopamine receptor imaging. Ann Nucl Med. 2003; 16(7):467-75. DOI: 10.1007/BF02988643. View

16.

Villar-Menendez I, Blanch M, Tyebji S, Pereira-Veiga T, Albasanz J, Martin M . Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington's disease. Neuromolecular Med. 2013; 15(2):295-309. DOI: 10.1007/s12017-013-8219-0. View

17.

Wei C, Singer P, Coelho J, Boison D, Feldon J, Yee B . Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning. Learn Mem. 2011; 18(7):459-74. PMC: 3125615. DOI: 10.1101/lm.2136011. View

18.

Bagga P, Chugani A, Patel A . Neuroprotective effects of caffeine in MPTP model of Parkinson's disease: A (13)C NMR study. Neurochem Int. 2015; 92:25-34. DOI: 10.1016/j.neuint.2015.11.006. View

19.

Hauser R, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M . Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol. 2011; 10(3):221-9. DOI: 10.1016/S1474-4422(11)70012-6. View

20.

Aarsland D, Pahlhagen S, Ballard C, Ehrt U, Svenningsson P . Depression in Parkinson disease--epidemiology, mechanisms and management. Nat Rev Neurol. 2011; 8(1):35-47. DOI: 10.1038/nrneurol.2011.189. View