Rafael Franco1,2*
Gemma Navarro1,3
- 1Department of Biochemistry and Molecular Biomedicine, School of Biology, Universidad de Barcelona, Barcelona, Spain
- 2Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
- 3Department of Biochemistry and Physiology, Faculty of Pharmacy, Universitat de Barcelona, Barcelona, Spain
Background
In this opinion paper, we provide scientific-based reasons about the huge therapeutic potential of adenosine A2A receptor antagonists, and about the huge challenges to demonstrate efficacy in clinical trials, i.e., to provide data now required to approve a new medication by the regulatory bodies, such as U.S. Food and Drug Administration (FDA).
Adenosine is an autacoid present in all tissue and body fluids. Adenosine, whose extracellular concentration is controlled by producing/degrading enzymes and by nucleoside transporters, acts via four (A1, A2A, A2B, and A3) specific cell surface receptors that belong to the superfamily of G-protein-coupled receptors. For decades, adenosine receptors have shown promise as targets of medications for a variety of ailments. Until recently, however, the only approved medicine was adenosine itself, i.e., the endogenous agonist, to combat arrhythmias, such as paroxysmal supraventricular tachycardia (1–3). Prospects are changing as the first medication targeting selectively the adenosine A2A receptor has been approved few years ago in Japan. The recently approved drug is an antagonist, i.e., a receptor blocker (see later). A2A receptor antagonists show promise in neuroprotection, although for Huntington’s or Niemann Pick’s diseases it is suggested that antagonists may be detrimental and/or there is controversy on which is the efficacious intervention, i.e., receptor activation or blockade [see Ref. (4–9) and references therein].
Potential of A2A Receptor Ligands in the Therapy of Neurodegenerative Diseases
At present, not only the A2A receptor (A2AR) is at the center stage for increasing the therapeutic tools in a variety of clinical indications, but this opinion paper focuses on the A2AR antagonists, which shows promise in immune-mediated control of cancer progression (10–13), in atrial fibrillation (14, 15), and in fighting against neurodegenerative diseases (see later). It is relevant that virtually all the selective A2AR antagonists whose toxicity has been tested in animal models are very safe. Safety has been confirmed in the clinical trials performed using different structures [e.g., Ref. (16, 17)]. Istradefylline (KW-6002) is one of the most studied antagonists; it is safe and efficacious in Parkinson’s disease. Accordingly, it was approved in Japan in 2013 for adjunctive treatment of Parkinson’s patients (under the Nouriast™) (18–20). To our knowledge, up to five clinical trials with different antagonists were or are being undertaken (18, 21), but none of them has yet got the approval by the U.S. FDA. In our opinion, the two main reasons of the difficulties in translating very promising preclinical assays into medications are (i) the tight requirements and (ii) the urgent need of efficacious approaches to assess neurodegeneration/neuroprotection in humans. It is commented in drug discovery forums that quite a number of current drugs could not pass today the tight requirements posed by the regulatory bodies. The issue of assessing how to measure the neuroprotective efficacy of a drug is commented later.
Parkinson’s and Alzheimer’s are the most extended neurodegenerative diseases in modern societies with high life expectancy (22, 23). With some exceptions of early-onset symptoms (24), age is the main factor for triggering the clinical symptoms (25–28). Whereas, Parkinson’s disease patients have successful dopamine-replacement therapies and other tools that may be used in the disease progression or to decrease the appearance of the medication side effects (29–31), Alzheimer’s disease patients have not yet got any really efficacious therapeutic drug/tool (32, 33).
Clinical manifestation of Parkinson’s disease occurs when a significant number of nigral dopamine-producing neurons have disappeared. Natural aging leads to 18% of loss of tyrosine hydroxylase-positive neurons in the nigra, whereas the degree of denervation in patients is very wide, going from 50 to 90%, even shortly after diagnosis (34). In this study in post-mortem samples, the authors state: “with several of the short-duration subjects showing comparable, severe loss of tyrosine hydroxylase-positive neurons to that seen in subjects 20 years, post-diagnosis” (34). The idea behind the use of A2AR antagonists in this disease is the adenosine-dopamine antagonism (35–37) in the striatum, where the expression of A2ARs is highest in the whole mammalian body (38). Therefore, dopamine-replacement therapy may be potentiated by the blockade of the A2AR. Indeed, Nouriast™ may serve to achieve efficacy of dopamine-replacement therapies at lower levels of dopaminergic drugs, such as levodopa. But the key point is that whereas levodopa is not neuroprotective, several preclinical assays indicate that A2AR antagonists show neuroprotective effects [see Ref. (39–42)]. Moreover, transgenic A2AR animals are more resistant to neurodegeneration induced by either 1-methyl-4-phenyl-1,2,3,6 tetra-hydropyridine (MPTP)-induced nigral lesion or focal cerebral ischemia (43–46). Further to those preclinical results, epidemiological studies showed that caffeine, which is a mixed/non-selective adenosine receptor antagonist, decrease the risk of suffering from Parkinson’s or from Alzheimer’s diseases [(47, 48); see Ref. (49) and references therein for review]. In summary, one challenge for the progression of A2AR antagonist into approved drugs is to demonstrate neuroprotection in humans, for instance to decrease the death rate of nigral dopaminergic neurons.
Challenges in Developing Neuroprotective Medicines
Based on development of our profession of translational research we notice that, often, scientific reports do not distinguish among symptom improvement and disease modifying drugs. Any drug that “improves” the condition of a parkinsonian animal model may be considered as neuroprotective. When the drug faces a clinical trial with patients, the promoter has to decide between analyzing symptom improvement and disease progression as primary outcome measure. For reasons further specified below, clinical trials for common neurodegenerative diseases analyze symptoms as primary outcome with a further difficulty: for ethical reasons patients should continue to take the ad hoc medication. Therefore, it is difficult to address whether any new medicine is improving symptoms or decreasing the side effects. For instance, parkinsonian patients recruited for clinical trials continue taking levodopa; thus, the assayed new drug must improve symptoms or reduce side effects appearing after years of taking levodopa. Difficulties in approving disease modifying, i.e., neuroprotective, medication for Parkinson’s were already noticed and reviewed years ago (50). Although the issue is on the table, to our knowledge there is not any effective action for neurodegenerative diseases unlike the case of rare diseases for which drug approval may be accelerated. There is an apparent lack of consensual rules to evaluate, and consequently approve, drugs whose action is to prevent neuronal death, i.e., drugs that modify the progression of a neurodegenerative disease. Apart from hoping for specific measures tackling this issue at the regulatory level, we think that (i) we are quickly moving to have reliable neuroprotection biomarkers with positron emission tomography resolution, i.e., to monitor neurodegeneration in vivo in humans and (ii) regulatory bodies should consider the approval of the use of safe drugs in healthy cohorts to assess the long-term potential as neuroprotectants (assumption would be that drug should delay clinical symptoms and/or delay neurodegenerative disease progression). The latter may seem risky but, again in our opinion, not riskier than taking food supplements or drug supplements to “combat aging,” such as testosterone.
Challenges in Designing Neuroprotective A2AR Antagonists
The two sides of drug action, i.e., addressing symptoms and disease progression, should be considered for any drug type (A2AR antagonists in this article). Whereas in the case of Parkinson’s disease, the targets of antagonists in adjunctive treatments of dopamine-replacement therapies are A2AR receptors in neurons, the A2A receptor containing targeted cells in the MPTP model of Parkinson’s disease that could be responsible for the neuroprotective action could not be determined in transgenic animals with cell-type-specific (conditional) deletion of the receptor (46). In this scenario, and based in convergent and wide experimental evidence, we consider that the role of the A2A receptor expressed in microglia should not be neglected. Hence, another challenge is to select (for a given disease) the receptor to be targeted, but also the cell where the receptor must be targeted and/or when the receptor of a given cell (neuron or glia) must be targeted to afford neuroprotection. Years ago, we found a relevant A2AR-related side result on studying gene expression in samples from Alzheimer’s patients. Genomics-relevant results were upregulation in samples from patients of the Kv3.4 voltage-gated potassium channel (51) and of the adenosine A1 receptor (52). Interestingly, when we moved to perform immunostaining in the cerebral cortex and hippocampus from necropsies of Alzheimer’s disease (AD) patients, we confirmed the upregulation of the adenosine A2A receptor concomitant with a change in the pattern of expression. The receptor was found inter alia in degenerating structures, i.e., in both dystrophic neurites and neurons exhibiting neurofibrillary tangles. Whereas, specific mRNA expression in the assayed brain areas was not different from that found in control samples, the microglial expression of the protein was negligible or absent in control samples but was evidently expressed in microglial cells in both the cerebral cortex and the hippocampus of patients (52).
Function of immune cells in the periphery and of microglia in the CNS is regulated by the A2AR. Due to the extensive work of M. Sitkovsky’s and other laboratories devoted to targeting adenosine receptors to combat cancer, the already promising immunotherapy to combat certain tumor types, may be enhanced by the blockade of A2AR expressed in immune cells (10–13). Provided that ATP is degraded to adenosine in oxygen partial deficiency and/or cell death occurring in degenerating environments, increased adenosine levels activate upregulated microglial A2ARs. Therefore, an obligate drug discovery approach is to target those cells and those receptors that promote M2-skewed microglial responses.
We highlight microglia as the most likely cell type to be targeted (for neuroprotection) by A2AR antagonists. Straightforward data in different models, support the view that A2AR activation in glia drives neuroinflammation and, therefore, the selective blockade of this receptor may be neuroprotective (40, 53–58). We think that more experimental effort is required to define when and how A2AR antagonists may achieve conversion from M1-skewed (proinflammatory) to M2-skewed (neuroprotective) microglia, something that requires control of the production of cytokines/chemokines, interferon-gamma, etc. [see (59) for review]. Intrinsic to any transformation, in this case into M1 or into M2 cells, there is a time window of opportunity whose starting point and duration should be also explored. In other words, when to start the application of the intervention and when it is too late.
We would like to end this paper with a further opinion, which A2AR antagonists may “conceptually” be the new beta-blockers (ß-adrenergic antagonists) whose therapeutic potential is vast from cardiovascular problems to asthma.
Author Contributions
The two authors participated in the conceptual design of this opinion article. RF did literature search. The two authors contributed to the writing and carefully checked English spelling/grammar.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding
Partially supported by grant BFU-2015-64405-R from Spanish Ministry of Economy and Competitiveness (may include EU FEDER funds).
References
1. Bailey AM, Baum RA, Rose J, Humphries RL. High-dose adenosine for treatment of refractory supraventricular tachycardia in an emergency department of an academic medical center: a case report and literature review. J Emerg Med (2016) 50:477–81. doi:10.1016/j.jemermed.2015.11.012
2. DiMarco JP, Miles W, Akhtar M, Milstein S, Sharma AD, Platia E, et al. Adenosine for paroxysmal supraventricular tachycardia: dose ranging and comparison with verapamil. Assessment in placebo-controlled, multicenter trials. The adenosine for PSVT Study Group. Ann Intern Med (1990) 113:104–10. doi:10.7326/0003-4819-113-2-104
3. Lerman BB. Mechanism, diagnosis, and treatment of outflow tract tachycardia. Nat Rev Cardiol (2015) 12:597–608. doi:10.1038/nrcardio.2015.121
4. Chiu F-LL, Lin J-TT, Chuang C-YY, Chien T, Chen C-MM, Chen K-HH, et al. Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington’s disease iPSCs. Hum Mol Genet (2015) 24:6066–79. doi:10.1093/hmg/ddv318
5. Lee C, Chern Y. Adenosine receptors and Huntington’s disease. Int Rev Neurobiol (2014) 119:195–232. doi:10.1016/B978-0-12-801022-8.00010-6
6. Leiva A, Guzmán-Gutiérrez E, Contreras-Duarte S, Fuenzalida B, Cantin C, Carvajal L, et al. Adenosine receptors: modulators of lipid availability that are controlled by lipid levels. Mol Aspects Med (2017) 55:26–44. doi:10.1016/j.mam.2017.01.007
7. Li W, Silva HB, Real J, Wang Y-M, Rial D, Li P, et al. Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington’s disease models. Neurobiol Dis (2015) 79:70–80. doi:10.1016/j.nbd.2015.03.030
8. Popoli P, Blum D, Domenici MR, Burnouf S, Chern Y. A critical evaluation of adenosine A2A receptors as potentially “druggable” targets in Huntington’s disease. Curr Pharm Des (2008) 14:1500–11. doi:10.2174/138161208784480117
9. Tyebji S, Saavedra A, Canas PM, Pliassova A, Delgado-García JM, Alberch J, et al. Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington’s disease. Neurobiol Dis (2015) 74:41–57. doi:10.1016/j.nbd.2014.11.004
10. Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr Opin Pharmacol (2016) 29:90–6. doi:10.1016/j.coph.2016.06.009
11. Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol (2012) 3:190. doi:10.3389/fimmu.2012.00190
12. Ohta A, Sitkovsky M. Methylxanthines, inflammation, and cancer: fundamental mechanisms. Handb Exp Pharmacol (2011) 200:469–81. doi:10.1007/978-3-642-13443-2_19
13. Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res (2014) 2:598–605. doi:10.1158/2326-6066.CIR-14-0075
14. Hove-Madsen L, Prat-Vidal C, Llach A, Ciruela F, Casadó V, Lluis C, et al. Adenosine A2A receptors are expressed in human atrial myocytes and modulate spontaneous sarcoplasmic reticulum calcium release. Cardiovasc Res (2006) 72:292–302. doi:10.1016/j.cardiores.2006.07.020
15. Llach A, Molina CE, Prat-Vidal C, Fernandes J, Casado V, Ciruela F, et al. Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A 2A receptors. Eur Heart J (2011) 32:721–9. doi:10.1093/eurheartj/ehq464
16. Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, 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) 13:767–76. doi:10.1016/S1474-4422(14)70148-6
17. Mizuno Y, Kondo T. Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord (2013) 28:1138–41. doi:10.1002/mds.25418
18. Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF. Adenosine, adenosine A 2A antagonists, and Parkinson’s disease. Parkinsonism Relat Disord (2009) 15:406–13. doi:10.1016/j.parkreldis.2008.12.006
19. Kondo T, Mizuno Y, Japanese Istradefylline Study Group. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol (2015) 38:41–6. doi:10.1097/WNF.0000000000000073
20. Navarro G, Borroto-Escuela DODO, Fuxe K, Franco R. Purinergic signaling in Parkinson’s disease. Relevance for treatment. Neuropharmacology (2015) 104:161–8. doi:10.1016/j.neuropharm.2015.07.024
21. Jenner P. An overview of adenosine A2A receptor antagonists in Parkinson’s disease. Int Rev Neurobiol (2014) 119:71–86. doi:10.1016/B978-0-12-801022-8.00003-9
22. Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson’s disease. Mov Disord (2014) 29:454–62. doi:10.1002/mds.25844
23. Reitz C, Mayeux R. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol (2014) 88:640–51. doi:10.1016/j.bcp.2013.12.024
24. Calderón-Garcidueñas L, Franco-Lira M, Mora-Tiscareño A, Medina-Cortina H, Torres-Jardón R, Kavanaugh M. Early Alzheimer’s and Parkinson’s disease pathology in Urban children: friend versus Foe responses—it is time to face the evidence. Biomed Res Int (2013) 2013:1–16. doi:10.1155/2013/161687
25. Adalbert R, Coleman MP. Review: axon pathology in age-related neurodegenerative disorders. Neuropathol Appl Neurobiol (2013) 39:90–108. doi:10.1111/j.1365-2990.2012.01308.x
26. Calabrese V, Santoro A, Monti D, Crupi R, Di Paola R, Latteri S, et al. Aging and Parkinson’s disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic Biol Med (2018) 115:80–91. doi:10.1016/j.freeradbiomed.2017.10.379
27. Coria F, Rubio I, Bayon C. Alzheimer’s disease, beta-amyloidosis, and aging. Rev Neurosci (1994) 5:275–92. doi:10.1515/REVNEURO.1994.5.4.275
28. Tanzi RE. A genetic dichotomy model for the inheritance of Alzheimer’s disease and common age-related disorders. J Clin Invest (1999) 104:1175–9. doi:10.1172/JCI8593
29. Birkmayer W, Hornykiewicz O. Additional experimental studies on L-DOPA in Parkinson’s syndrome and reserpine parkinsonism. Arch Psychiatr Nervenkr (1964) 206:367–81. doi:10.1007/BF00341704
30. Hornykiewicz O. The discovery of dopamine deficiency in the parkinsonian brain. J Neural Transm Suppl (2006) 70:9–15. doi:10.1007/978-3-211-45295-0_3
31. Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Bonucelli U, et al. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord (2004) 19:997–1005. doi:10.1002/mds.20243
32. Féger J, Hirsch EC. In search of innovative therapeutics for neuropsychiatric disorders: the case of neurodegenerative diseases. Ann Pharm Fr (2015) 73:3–12. doi:10.1016/j.pharma.2014.10.001
33. Franco R, Cedazo-Minguez A. Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Front Pharmacol (2014) 5:146. doi:10.3389/fphar.2014.00146
34. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain (2013) 136:2419–31. doi:10.1093/brain/awt192
35. Fuxe K, Strömberg I, Popoli P, Rimondini-Giorgini R, Torvinen M, Ogren SO, et al. Adenosine receptors and Parkinson’s disease. Relevance of antagonistic adenosine and dopamine receptor interactions in the striatum. Adv Neurol (2001) 86:345–53.
36. Josselyn SA, Beninger RJ. Behavioral effects of intrastriatal caffeine mediated by adenosinergic modulation of dopamine. Pharmacol Biochem Behav (1991) 39:97–103. doi:10.1016/0091-3057(91)90403-O
37. Wood PL, Kim HS, Boyar WC, Hutchison A. Inhibition of nigrostriatal release of dopamine in the rat by adenosine receptor agonists: A1 receptor mediation. Neuropharmacology (1989) 28:21–5. doi:10.1016/0028-3908(89)90062-2
38. Rosin DL, Robeva A, Woodard RL, Guyenet PG, Linden J. Immunohistochemical localization of adenosine A 2A receptors in the rat central nervous system. J Comp Neurol (1998) 401:163–86. doi:10.1002/(SICI)1096-9861(19981116)401
39. Chen J-F, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, et al. Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Prog Neurobiol (2007) 83:310–31. doi:10.1016/j.pneurobio.2007.09.002
40. Chen J-F, Pedata F. Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des (2008) 14:1490–9. doi:10.2174/138161208784480126
41. Sebastião AM, Ribeiro JA. Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection. Br J Pharmacol (2009) 158:15–22. doi:10.1111/j.1476-5381.2009.00157.x
42. Stone TW, Ceruti S, Abbracchio MP. Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol (2009) 193:535–87. doi:10.1007/978-3-540-89615-9_17
43. Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, et al. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci (1999) 19:9192–200.
44. Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson’s disease. J Neurosci (2001) 21:RC143.
45. Gui L, Duan W, Tian H, Li C, Zhu J, Chen J-F, et al. Adenosine A2A receptor deficiency reduces striatal glutamate outflow and attenuates brain injury induced by transient focal cerebral ischemia in mice. Brain Res (2009) 1297:185–93. doi:10.1016/j.brainres.2009.08.050
46. Xu K, Di Luca DG, Orrú M, Xu Y, Chen J-F, Schwarzschild MA. Neuroprotection by caffeine in the MPTP model of Parkinson’s disease and its dependence on adenosine A 2A receptors. Neuroscience (2016) 322:129–37. doi:10.1016/j.neuroscience.2016.02.035
47. Ross G, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA (2000) 283:2674–9. doi:10.1001/jama.283.20.2674
48. Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol (2002) 9:377–82. doi:10.1046/j.1468-1331.2002.00421.x
49. Oñatibia-Astibia A, Franco R, Martínez-Pinilla E. Health benefits of methylxanthines in neurodegenerative diseases. Mol Nutr Food Res (2017) 61:1600670. doi:10.1002/mnfr.201600670
50. Olanow CW, Kieburtz K, Schapira AHV. Why have we failed to achieve neuroprotection in Parkinson’s disease? Ann Neurol (2008) 64:S101–10. doi:10.1002/ana.21461
51. Angulo E, Noé V, Casadó V, Mallol J, Gomez-Isla T, Lluis C, et al. Up-regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer’s disease. J Neurochem (2004) 91:547–57. doi:10.1111/j.1471-4159.2004.02771.x
52. Angulo E, Casadó V, Mallol J, Canela EI, Viñals F, Ferrer I, et al. A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain Pathol (2003) 13:440–51. doi:10.1111/j.1750-3639.2003.tb00475.x
53. Abbracchio MP, Cattabeni F. Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases. Ann N Y Acad Sci (1999) 890:79–92. doi:10.1111/j.1749-6632.1999.tb07983.x
54. Brambilla R, Cottini L, Fumagalli M, Ceruti S, Abbracchio MP. Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia (2003) 43:190–4. doi:10.1002/glia.10243
55. Gyoneva S, Shapiro L, Lazo C, Garnier-Amblard E, Smith Y, Miller GW, et al. Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson’s disease. Neurobiol Dis (2014) 67:191–202. doi:10.1016/j.nbd.2014.03.004
56. Minghetti L, Greco A, Potenza RL, Pezzola A, Blum D, Bantubungi K, et al. Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration. J Neuropathol Exp Neurol (2007) 66:363–71. doi:10.1097/nen.0b013e3180517477
57. Nobre HV, de Andrade Cunha GM, de Vasconcelos LM, Magalhães HIF, Neto RNO, Maia FD, et al. Caffeine and CSC, adenosine A2A antagonists, offer neuroprotection against 6-OHDA-induced neurotoxicity in rat mesencephalic cells. Neurochem Int (2010) 56:51–8. doi:10.1016/j.neuint.2009.09.001
58. Saura J, Angulo E, Ejarque A, Casado V, Tusell JM, Moratalla R, et al. Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia. J Neurochem (2005) 95:919–29. doi:10.1111/j.1471-4159.2005.03395.x
Keywords: neuroprotection, astroglia and microglia, neuronal death, Alzheimer’s and Parkinson’s disease, human, clinical trials as topic, caffeine
Citation: Franco R and Navarro G (2018) Adenosine A2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges. Front. Psychiatry 9:68. doi: 10.3389/fpsyt.2018.00068
Received: 28 October 2017; Accepted: 19 February 2018;
Published: 12 March 2018
Edited by:
Manuella P. Kaster, Universidade Federal de Santa Catarina, BrazilReviewed by:
Filipe Marques Goncalves, Albert Einstein College of Medicine, United StatesCopyright: © 2018 Franco and Navarro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rafael Franco, rfranco@ub.edu