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Current Research and Role of A2A Receptors in Parkinson's Disease


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Current Research and Role of A2A Receptors in Parkinson's Disease

Introduction

The adenosine receptors (ARs) in the nervous system act as a kind of “go-between” to regulate the release of neurotransmitters and the action of neuromodulators. Receptor-receptor interactions and AR-transporter interplay occur as part of the adenosine’s attempt to control synaptic transmission[1]. A2A receptor (A2AR) is highly expressed throughout the brain and A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases[2]. A2AR is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5, and adenosine A1 receptors. It has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson’s disease (PD)[3].

Proposed mechanism of symptomatic anti-parkinsonian activity of A2A receptor antagonists
(Schwarzschild M A., et al. Trends in Neurosciences, 2006)

1. A2ARs in the Brain

Adenosine is an essential neuromodulatory molecule in the brain and exerts its action through activation of four G-protein coupled adenosine receptors, A1, A2A, A2B, and A3 receptors[4]. In the brain, A2ARs are primarily localized in the striatum, olfactory tubercle, and the nucleus accumbens[5]. Adenosine receptors have been shown to have both a presynaptic and postsynaptic neuromodulatory effect. A1Rs induce synaptic depression through reducing neurotransmitter release[6], whereas A2ARs are associated with increasing neurotransmitter release[7]. In some areas of the brain, including the substantia nigra (SN) and striatum, the lower affinity A2ARs can be highly expressed, and have an excitatory neuromodulatory effect[8]. This excitatory effect may be in part due to the ability of the A2AR to increase the expression of the calcium-permeable GluA1 subunit of the AMPA receptor through the activation of PKA[9].

2. Current pharmacotherapy for Parkinson’s disease

PD is a basal ganglia-associated disorder that affects 1-2% of individuals over 60 years of age. The main symptoms of the disease are motor-related, including reduced spontaneous movement, akinesia (lack of movement), bradykinesia (slowness of movements), rigidity (due to increased muscular tone), as well as the characteristic resting tremor[10]. Current pharmacotherapy of PD can be both highly effective and largely inadequate. In earlier studies, by boosting dopamine-mediated transmission, these strategies can dramatically (albeit partially) alleviate the motor deficits in PD. And a number of dopamine agonists has revolutionized the clinical management of PD. However, even the most effective antiparkinsonian drugs only provide symptomatic relief. Furthermore, as the disease continues to progress, troublesome side effects generally appear several years after initiation of pharmacological treatment, including motor fluctuations (on-off phenomena) and L-DOPA-induced dyskinesias. The inadequacies and adverse effects of drugs that target the dopaminergic system have prompted a search for alternative or adjunctive approaches that can modulate basal ganglia motor circuitry with a reduced risk of side effects. Antagonists of adenosine A2A receptors have recently emerged as a leading candidate class of nondopaminergic anti-parkinsonian agents.

3. Role of A2ARs in Parkinson's disease

The A2ARs are highly expressed in the basal ganglia and depend on Gs and other interacting proteins for correct transduction of their signals[11]. The striatum is the anatomical region in mammals that most strongly expresses A2ARs, which are thought to fulfill an important role in the regulation of dopaminergic transmission in the basal ganglia[12]. Adenosine A2AR-mediated activity is usually antagonistic to that mediated by striatal D2R in MSNs. Indeed, the functional antagonism between A2A and D2 receptors was recently reported in striatal cholinergic interneurons[13]. Overall, adenosine-dopamine antagonism underlies the potential therapeutic benefits of A2AR-selective antagonists in PD. More and more evidences suggest that A2AR-containing heteromers may be the real targets of therapeutic agents used to combat basal ganglia disorders from the beginning of the 21st century[14]. Receptor heteromers are the focus of intense research since through heteromerization, receptors become unique functional entities with different properties from those of each of the receptors involved. The A2AR-D2R heteromer has been reported in animal models of PD. Moreover, A2AR antagonists proposed for the treatment of PD may target A2ARcontaining heteromers[15].

4. A2A antagonists as potential neuroprotectants in PD

In Parkinson’s disease, A2ARs have been implicated in the pathology and development of the disease. Neurochemical evidence that A2A receptors functionally oppose the actions of dopamine D2 receptors on GABAergic striatopallidal neurons raised the possibility that A2A antagonists might boost the anti-parkinsonian action of dopamine-replacement strategies[16]. Recently, clinical trials have explored the role of adenosine A2AR antagonists, namely Istradefylline, as an adjunct therapy to reduce these side effects, with recent success[17]. In addition, several on-going clinical trials are investigating the potential use of A2AR antagonist, in slowing the progression of PD symptoms[18]. There are some examples of the A2AR antagonist recent clinically tested for Parkinson’s disease[19]. To date, the A2AR antagonist, Istradefylline, is in Phase 3 clinical trials in Japan for Parkinson’s disease.

Drug Name Clinical Trial Results
Istradefylline Study of Istradefylline for the treatments of Parkinson’s disease in patients taking levodopa, Phase 3 (NCT00955526) Completed
Long-term study of Istradefylline in Parkinson’s disease patients, Phase 3 (NCT00957203) Completed
A 12-week randomized study to evaluate oral Istradefylline in subjects with moderate to severe Parkinson’s disease, Phase 3 (NCT01968031) Completed
The effects of mild Hepatic impairment on the pharmacokinetics of Istradefylline, Phase 1 (NCT02256033) Completed
An extension of Istradefylline in North American Parkinson’s disease patients who have completed study 6002-INT-001, Phase 3 (NCT00199381) Terminated
The effects of rifampin on the metabolism of Istradefylline in healthy volunteers, Phase 1 (NCT02174250) Completed
Preladenant A placebo- and active-controlled study of preladenant in early Parkinson’s disease, Phase 3 (NCT01155479) Terminated
A placebo- and active-controlled study of preladenant in subjects with moderate or severe Parkinson’s disease, Phase 3 (NCT01155466) Completed
A dose finding study of preladenant for the treatment of Parkinson’s disease, Phase 2 (NCT01294800) Completed
SYN-115 Safety and efficacy study of SYN-115 in Parkinson’s disease patients using levodopa to treat end of dose wearing off, Phase 2 & 3 (NCT01283594) Completed

A2A antagonists are used in preclinical trials and potential role in Parkinson’s disease
(Stockwell J., et al. Molecules., 2017)

Summary and Expectation

In recent years, understanding of the role of the A2AR in both normal physiological conditions and in neurodegenerative diseases has grown substantially, and novel research may allow for the identification of better therapeutic strategies. On the one hand, clinical development of A2A antagonists as anti-parkinsonian agents should also take into account evidence for A2A receptor involvement in common nonmotor CNS disorders in PD patients, such a depression, psychosis, dementia and disrupted arousal and sleep states. On the other hand, the well-established peripheral effects of A2A receptors, particularly their anti-inflammatory actions, must also be addressed in the clinical development of A2A antagonists, especially in advanced PD patients who are at higher risk of and from infections. Finally, although the promise of these compounds is counterbalanced by the long odds inherent in clinical drug development, A2A antagonism clearly offers a uniquely hopeful and realistic opportunity for improving PD treatment.

References:

  1. Sebastiäo AM, Ribeiro JA. Adenosine receptors and the central nervous system [J]. Handb Exp Pharmacol, 2009, 193: 471-534.
  2. Cunha RA. Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade. Purinergic Signal. 2005, 1, 111-134.
  3. Schwarzschild M A, Agnati L, Fuxe K, et al. Targeting adenosine A2A receptors in Parkinson's disease.[J]. Trends in Neurosciences, 2006, 29(11):647.
  4. Fredholm BB, Chen JF, Cunha RA, et al. Adenosine and brain function. Int. Rev. Neurobiol. 2005, 63, 191-270.
  5. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci. 2001, 24, 31-55.
  6. Rebol, N, Coelho JE, Costenla AR, et al. Decrease of adenosine A1 receptor density and of adenosine neuromodulation in the hippocampus of kindled rats. Eur. J. Neurosci. 2003, 18, 820-828.
  7. Popoli P, Betto P, Reggio R, et al. Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats. Eur. J. Pharmacol. 1995, 287, 215-217.
  8. Bogenpohl JW, Ritter SL, Hall RA, et al. Adenosine A2A receptor in the monkey basal ganglia: Ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum. J. Comp. Neurol. 2012, 520, 570-589.
  9. Dias RB, Ribeiro JA, Sebastiao AM. Enhancement of AMPA currents and GluR1 membrane expression through PKA-coupled adenosine A2A receptors. Hippocampus 2012, 22, 276-291.
  10. Simola N, Morelli M, Pinna A. Adenosine A2A Receptor Antagonists and Parkinsons Disease: State of the Art and Future Directions[J]. Current Pharmaceutical Design, 2008, 14(15):1475-89.
  11. Burgueño J, Blake D J, Benson MA, et al. The adenosine A2A receptor interacts with the actin-binding protein alpha-actinin. J Biol Chem. 2003, 278, 37545-37552.
  12. Morelli M, Carta AR, Jenner P. Adenosine A2A receptors and Parkinson's disease. Handb Exp Pharmacol. 2009, 193, 589-615.
  13. Tozzi A, de Iure A, Di Filippo M, et al. The distinct role of medium spiny neurons and cholinergic interneurons in the D2/A2A receptor interaction in the striatum: Implications for Parkinson's disease. J Neurosci. 2011, 31,1850-1862
  14. Ferré S, Baler R, Bouvier M. et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol. 2009, 5, 131-134.
  15. Casadó V, Cortés A, Mallol J. et al. GPCR homomers and heteromers: A better choice as targets for drug development than GPCR monomers? Pharmacol Ther. 2009, 124, 248–257.
  16. Ferré S, O'Connor W T, Fuxe K, et al. The striopallidal neuron: a main locus for adenosine-dopamine interactions in the brain[J]. Journal of Neuroscience the Official Journal of the Society for Neuroscience, 1993, 13(12):5402-6.
  17. Uchida SI; Tashiro T, Kawai-Uchida, et al. The Adenosine A 2A-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.
  18. Wills A M, Eberly S, Tennis M, et al. Caffeine consumption and risk of dyskinesia in CALM-PD.[J]. Movement Disorders Official Journal of the Movement Disorder Society, 2013, 28(3):380.
  19. Stockwell J, Jakova E, Cayabyab F S. Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration.[J]. Molecules, 2017, 22(4):676.

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