{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:48:39Z","timestamp":1774874919304,"version":"3.50.1"},"reference-count":107,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"La Caixa Foundation","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"La Caixa Foundation","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"La Caixa Foundation","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"La Caixa Foundation","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"Centro 2020","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"Centro 2020","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"Centro 2020","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"Centro 2020","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"Centro 2020","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"FCT","award":["LCF\/PR\/HP17\/52190001"],"award-info":[{"award-number":["LCF\/PR\/HP17\/52190001"]}]},{"name":"FCT","award":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"],"award-info":[{"award-number":["CENTRO-01-0145-FEDER-000008:BrainHealth2020"]}]},{"name":"FCT","award":["CENTRO-01-0246-FEDER-000010"],"award-info":[{"award-number":["CENTRO-01-0246-FEDER-000010"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-03127"],"award-info":[{"award-number":["POCI-01-0145-FEDER-03127"]}]},{"name":"FCT","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adenosine A2A receptor (A2AR) antagonists are the leading nondopaminergic therapy to manage Parkinson\u2019s disease (PD) since they afford both motor benefits and neuroprotection. PD begins with a synaptic dysfunction and damage in the striatum evolving to an overt neuronal damage of dopaminergic neurons in the substantia nigra. We tested if A2AR antagonists are equally effective in controlling these two degenerative processes. We used a slow intracerebroventricular infusion of the toxin MPP+ in male rats for 15 days, which caused an initial loss of synaptic markers in the striatum within 10 days, followed by a neuronal loss in the substantia nigra within 30 days. Interestingly, the initial loss of striatal nerve terminals involved a loss of both dopaminergic and glutamatergic synaptic markers, while GABAergic markers were preserved. The daily administration of the A2AR antagonist SCH58261 (0.1 mg\/kg, i.p.) in the first 10 days after MPP+ infusion markedly attenuated both the initial loss of striatal synaptic markers and the subsequent loss of nigra dopaminergic neurons. Strikingly, the administration of SCH58261 (0.1 mg\/kg, i.p. for 10 days) starting 20 days after MPP+ infusion was less efficacious to attenuate the loss of nigra dopaminergic neurons. This prominent A2AR-mediated control of synaptotoxicity was directly confirmed by showing that the MPTP-induced dysfunction (MTT assay) and damage (lactate dehydrogenase release assay) of striatal synaptosomes were prevented by 50 nM SCH58261. This suggests that A2AR antagonists may be more effective to counteract the onset rather than the evolution of PD pathology.<\/jats:p>","DOI":"10.3390\/ijms25094903","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:30:49Z","timestamp":1714534249000},"page":"4903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Adenosine A2A Receptor Blockade Provides More Effective Benefits at the Onset Rather than after Overt Neurodegeneration in a Rat Model of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Ana Carla L.","family":"Nunes","sequence":"first","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Marta","family":"Carmo","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Andrea","family":"Behrenswerth","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"given":"Paula M.","family":"Canas","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-4945","authenticated-orcid":false,"given":"Paula","family":"Agostinho","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-6422","authenticated-orcid":false,"given":"Rodrigo A.","family":"Cunha","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S0896-6273(03)00568-3","article-title":"Parkinson\u2019s disease: Mechanisms and models","volume":"39","author":"Dauer","year":"2003","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrneurol.2016.152","article-title":"Advances in markers of prodromal Parkinson disease","volume":"12","author":"Postuma","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.expneurol.2012.01.011","article-title":"Axon degeneration in Parkinson\u2019s disease","volume":"246","author":"Burke","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"703","DOI":"10.3233\/JPD-160881","article-title":"Is axonal degeneration a key early event in Parkinson\u2019s disease?","volume":"6","author":"Kurowska","year":"2016","journal-title":"J. Parkinsons Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1002\/mds.26620","article-title":"Early synaptic dysfunction in Parkinson\u2019s disease: Insights from animal models","volume":"31","author":"Schirinzi","year":"2016","journal-title":"Mov. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0022-510X(73)90175-5","article-title":"Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations","volume":"20","author":"Bernheimer","year":"1973","journal-title":"J. Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1002\/ana.410260409","article-title":"Striatal dopamine deficiency in Parkinson\u2019s disease: Role of aging","volume":"26","author":"Scherman","year":"1989","journal-title":"Ann. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4732","DOI":"10.1523\/JNEUROSCI.18-12-04732.1998","article-title":"Plasticity of synapses in the rat neostriatum after unilateral lesion of the nigrostriatal dopaminergic pathway","volume":"18","author":"Ingham","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"14182","DOI":"10.1523\/JNEUROSCI.2149-10.2010","article-title":"Distinct levels of dopamine denervation differentially alter striatal synaptic plasticity and NMDA receptor subunit composition","volume":"30","author":"Picconi","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1002\/cne.22563","article-title":"Differential structural plasticity of corticostriatal and thalamostriatal axo-spinous synapses in MPTP-treated Parkinsonian monkeys","volume":"519","author":"Villalba","year":"2011","journal-title":"J. Comp. Neurol."},{"key":"ref_11","first-page":"625","article-title":"Frequency-dependent corticostriatal disinhibition resulting from chronic dopamine depletion: Role of local striatal cGMP and GABA-AR signaling","volume":"27","author":"Jayasinghe","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1007\/s12035-022-03162-1","article-title":"Increased ATP release and higher impact of adenosine A2A receptors on corticostriatal plasticity in a rat model of presymptomatic Parkinson\u2019s disease","volume":"60","author":"Matheus","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11441","DOI":"10.1073\/pnas.0702717104","article-title":"Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice","volume":"104","author":"Kitada","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.neuroscience.2009.01.021","article-title":"Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein","volume":"159","author":"Watson","year":"2009","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1093\/hmg\/ddu543","article-title":"LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory","volume":"24","author":"Volta","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.nbd.2015.07.009","article-title":"An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease","volume":"82","author":"Tagliaferro","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1093\/brain\/awz065","article-title":"Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration","volume":"142","author":"Durante","year":"2019","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e58997","DOI":"10.7554\/eLife.58997","article-title":"Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations","volume":"9","author":"Chen","year":"2020","journal-title":"eLife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1093\/brain\/awab242","article-title":"Dopamine-dependent early synaptic and motor dysfunctions induced by \u03b1-synuclein in the nigrostriatal circuit","volume":"144","author":"Tozzi","year":"2021","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s11302-020-09694-2","article-title":"The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson\u2019s disease","volume":"16","author":"Chen","year":"2020","journal-title":"Purinergic Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.tins.2006.09.004","article-title":"Targeting adenosine A2A receptors in Parkinson\u2019s disease","volume":"29","author":"Schwarzschild","year":"2006","journal-title":"Trends Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/978-3-540-89615-9_18","article-title":"Adenosine A2A receptors and Parkinson\u2019s disease","volume":"193","author":"Morelli","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1212\/01.WNL.0000095214.53646.72","article-title":"Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson\u2019s disease","volume":"61","author":"Schwarzschild","year":"2003","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.parkreldis.2008.12.006","article-title":"Adenosine, adenosine A2A antagonists, and Parkinson\u2019s disease","volume":"15","author":"Jenner","year":"2009","journal-title":"Park. Relat. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1111\/jnc.13724","article-title":"How does adenosine control neuronal dysfunction and neurodegeneration?","volume":"139","author":"Cunha","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1038\/ncomms11915","article-title":"Early synaptic deficits in the APP\/PS1 mouse model of Alzheimer\u2019s disease involve neuronal adenosine A2A receptors","volume":"7","author":"Haberl","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves, F.Q., Lopes, J.P., Silva, H.B., Lemos, C., Silva, A.C., Gon\u00e7alves, N., Tom\u00e9, \u00c2.R., Ferreira, S.G., Canas, P.M., and Rial, D. (2019). Synaptic and memory dysfunction in a \u03b2-amyloid model of early Alzheimer\u2019s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol. Dis., 132.","DOI":"10.1016\/j.nbd.2019.104570"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"ENEURO.0385-18.2018","DOI":"10.1523\/ENEURO.0385-18.2018","article-title":"Neuronal adenosine A2A receptors are critical mediators of neurodegeneration triggered by convulsions","volume":"5","author":"Canas","year":"2018","journal-title":"eNeuro"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.pneurobio.2007.05.001","article-title":"Adenosine A2A receptors and basal ganglia physiology","volume":"83","author":"Schiffmann","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/ana.21313","article-title":"Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms","volume":"63","author":"Yu","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuint.2009.09.001","article-title":"Caffeine and CSC, adenosine A2A antagonists, offer neuroprotection against 6-OHDA-induced neurotoxicity in rat mesencephalic cells","volume":"56","author":"Nobre","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_32","first-page":"718","article-title":"Adenosine A2A receptors modulate \u03b1-synuclein aggregation and toxicity","volume":"27","author":"Ferreira","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1111\/bph.14771","article-title":"Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A2A receptor over-activation in a rat model of Parkinson\u2019s disease","volume":"176","author":"Carmo","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.expneurol.2006.02.002","article-title":"Rat model of Parkinson\u2019s disease: Chronic central delivery of 1-methyl-4-phenylpyridinium (MPP+)","volume":"200","author":"Yazdani","year":"2006","journal-title":"Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S116","DOI":"10.1016\/j.parkreldis.2008.04.008","article-title":"Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson\u2019s disease","volume":"14","author":"Sonsalla","year":"2008","journal-title":"Park. Relat. Disord."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.neuropharm.2013.08.026","article-title":"Predominant loss of glutamatergic terminal markers in a \u03b2-amyloid peptide model of Alzheimer\u2019s disease","volume":"76 Pt A","author":"Canas","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1111\/bph.12234","article-title":"Functional interaction between pre-synaptic \u03b16\u03b22-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum","volume":"169","author":"Wopereis","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1100\/tsw.2009.143","article-title":"Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway","volume":"9","author":"Quiroz","year":"2009","journal-title":"Sci. World J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1111\/j.1471-4159.2009.05876.x","article-title":"GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A receptors","volume":"108","author":"Gomes","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1523\/JNEUROSCI.3574-05.2006","article-title":"Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers","volume":"26","author":"Ciruela","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1471-4159.2004.02887.x","article-title":"Co-localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum","volume":"92","author":"Rodrigues","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/0024-3205(89)90365-2","article-title":"Effects of MPTP, MPP+ and paraquat on mitochondrial potential and oxidative stress","volume":"44","author":"Lambert","year":"1989","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1111\/j.1471-4159.1990.tb01962.x","article-title":"Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on ATP levels of mouse brain synaptosomes","volume":"54","author":"Scotcher","year":"1990","journal-title":"J. Neurochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1002\/ana.21995","article-title":"Clinical progression in Parkinson disease and the neurobiology of axons","volume":"67","author":"Cheng","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1097\/01.WCB.0000126563.85360.75","article-title":"Changes of dopamine turnover in the progression of Parkinson\u2019s disease as measured by positron emission tomography: Their relation to disease-compensatory mechanisms","volume":"24","author":"Sossi","year":"2004","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/PL00022911","article-title":"Risk for Parkinson\u2019s disease: Twin studies for the detection of asymptomatic subjects using [18F]6-fluorodopa PET","volume":"247","author":"Laihinen","year":"2000","journal-title":"J. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1093\/brain\/aws133","article-title":"Alterations in axonal transport motor proteins in sporadic and experimental Parkinson\u2019s disease","volume":"135","author":"Chu","year":"2012","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1093\/brain\/awt192","article-title":"Disease duration and the integrity of the nigrostriatal system in Parkinson\u2019s disease","volume":"136","author":"Kordower","year":"2013","journal-title":"Brain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JPD-150769","article-title":"Retrograde axonal degeneration in Parkinson disease","volume":"6","author":"Tagliaferro","year":"2016","journal-title":"J. Parkinsons Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/0024-3205(89)90625-5","article-title":"Central depletion of dopamine in rats by 1-methyl-4-phenylpyridine","volume":"45","author":"Okada","year":"1989","journal-title":"Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bbr.2015.04.019","article-title":"The degeneration of dopaminergic synapses in Parkinson\u2019s disease: A selective animal model","volume":"289","author":"Morales","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Campanelli, F., Natale, G., Marino, G., Ghiglieri, V., and Calabresi, P. (2022). Striatal glutamatergic hyperactivity in Parkinson\u2019s disease. Neurobiol. Dis., 168.","DOI":"10.1016\/j.nbd.2022.105697"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11655","DOI":"10.1523\/JNEUROSCI.0288-13.2013","article-title":"Aberrant restoration of spines and their synapses in L-DOPA-induced dyskinesia: Involvement of corticostriatal but not thalamostriatal synapses","volume":"33","author":"Zhang","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1093\/brain\/awv018","article-title":"Reduced cortical innervation of the subthalamic nucleus in MPTP-treated parkinsonian monkeys","volume":"138","author":"Mathai","year":"2015","journal-title":"Brain"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/neur.1996.0018","article-title":"Synaptic plasticity in the caudate nucleus of patients with Parkinson\u2019s disease","volume":"5","author":"Anglade","year":"1996","journal-title":"Neurodegeneration"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1006\/exnr.2001.7730","article-title":"In vivo extracellular recording of striatal neurons in the awake rat following unilateral 6-hydroxydopamine lesions","volume":"171","author":"Chen","year":"2001","journal-title":"Exp. Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5283","DOI":"10.1523\/JNEUROSCI.1224-04.2004","article-title":"Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism","volume":"24","author":"Picconi","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1093\/cercor\/bhp317","article-title":"Cortical regulation of striatal medium spiny neuron dendritic remodeling in parkinsonism: Modulation of glutamate release reverses dopamine depletion-induced dendritic spine loss","volume":"20","author":"Garcia","year":"2010","journal-title":"Cereb. Cortex"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5316","DOI":"10.1038\/ncomms6316","article-title":"Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia","volume":"5","author":"Fieblinger","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"9629","DOI":"10.1073\/pnas.1606792113","article-title":"Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson\u2019s disease","volume":"113","author":"Singh","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/brain\/116.2.433","article-title":"Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson\u2019s disease","volume":"116","author":"Calabresi","year":"1993","journal-title":"Brain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nn1632","article-title":"Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models","volume":"9","author":"Day","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/978-3-7091-0932-8_24","article-title":"Synaptic dysfunction in Parkinson\u2019s disease","volume":"970","author":"Picconi","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00702-017-1735-6","article-title":"Loss and remodeling of striatal dendritic spines in Parkinson\u2019s disease: From homeostasis to maladaptive plasticity?","volume":"125","author":"Villalba","year":"2018","journal-title":"J. Neural Transm."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.neuron.2018.07.028","article-title":"A cortical pathogenic theory of Parkinson\u2019s disease","volume":"99","author":"Foffani","year":"2018","journal-title":"Neuron"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1046\/j.0022-3042.2001.00694.x","article-title":"Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson\u2019s disease","volume":"80","author":"Ikeda","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/j.1471-4159.2009.06425.x","article-title":"Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson\u2019s disease","volume":"111","author":"Carta","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"RC143","DOI":"10.1523\/JNEUROSCI.21-10-j0001.2001","article-title":"Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson\u2019s disease","volume":"21","author":"Chen","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.neuropharm.2004.11.009","article-title":"KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse","volume":"48","author":"Pierri","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"14741","DOI":"10.1523\/JNEUROSCI.3728-09.2009","article-title":"Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway","volume":"29","author":"Canas","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1471-4159.2009.06465.x","article-title":"Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life","volume":"112","author":"Cognato","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"7833","DOI":"10.1073\/pnas.1423088112","article-title":"Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress","volume":"112","author":"Kaster","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Shen, H.Y., Canas, P.M., Garcia-Sanz, P., Lan, J.Q., Boison, D., Moratalla, R., Cunha, R.A., and Chen, J.F. (2013). Adenosine A\u2082A receptors in striatal glutamatergic terminals and GABAergic neurons oppositely modulate psychostimulant action and DARPP-32 phosphorylation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080902"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.nbd.2011.08.030","article-title":"Adenosine A2a receptor antagonists attenuate striatal adaptations following dopamine depletion","volume":"45","author":"Peterson","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.expneurol.2009.01.010","article-title":"A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity","volume":"217","author":"Belcastro","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1523\/JNEUROSCI.22-05-01967.2002","article-title":"Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: Possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum","volume":"22","author":"Popoli","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/s41586-021-04059-0","article-title":"Disruption of mitochondrial complex I induces progressive parkinsonism","volume":"599","author":"Zampese","year":"2021","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"fcac165","DOI":"10.1093\/braincomms\/fcac165","article-title":"Linking \u03b1-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson\u2019s disease","volume":"4","author":"Kulkarni","year":"2022","journal-title":"Brain Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.tins.2022.11.007","article-title":"\u03b1-Synuclein in synaptic function and dysfunction","volume":"46","author":"Sharma","year":"2023","journal-title":"Trends Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1093\/cercor\/bhab244","article-title":"\u03b1-Synuclein selectively impairs motor sequence learning and value sensitivity: Reversal by the adenosine A2A receptor antagonists","volume":"32","author":"He","year":"2022","journal-title":"Cereb. Cortex"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Badanjak, K., Fixemer, S., Smaji\u0107, S., Skupin, A., and Gr\u00fcnewald, A. (2021). The contribution of microglia to neuroinflammation in Parkinson\u2019s disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094676"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.tins.2017.04.001","article-title":"The role of astrocyte dysfunction in Parkinson\u2019s disease pathogenesis","volume":"40","author":"Booth","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.nbd.2014.03.004","article-title":"Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson\u2019s disease","volume":"67","author":"Gyoneva","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"666710","DOI":"10.3389\/fnins.2021.666710","article-title":"Astrocytes and adenosine A2A receptors: Active players in Alzheimer\u2019s disease","volume":"15","author":"Lopes","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1038\/sj.bjp.0705185","article-title":"Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity","volume":"138","author":"Souza","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.nbd.2007.04.018","article-title":"Blockade of adenosine A2A receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons","volume":"27","author":"Silva","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_87","first-page":"204","article-title":"Blockade of adenosine A2A receptors prevents interleukin-1\u03b2-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway","volume":"9","author":"Duarte","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1111\/jnc.12050","article-title":"Neuroprotection afforded by adenosine A2A receptor blockade is modulated by corticotrophin-releasing factor (CRF) in glutamate injured cortical neurons","volume":"123","author":"Valadas","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.expneurol.2015.03.004","article-title":"Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis","volume":"267","author":"Ng","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1021\/cn200036s","article-title":"3-(Fur-2-yl)-10-(2-phenylethyl)-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one, a novel adenosine receptor antagonist with A2A-mediated neuroprotective effects","volume":"2","author":"Scatena","year":"2011","journal-title":"ACS Chem. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5772","DOI":"10.1021\/acs.jmedchem.7b00457","article-title":"The 1,2,4-Triazolo [4,3-a]pyrazin-3-one as a versatile scaffold for the design of potent adenosine human receptor antagonists. structural investigations to target the A2A receptor subtype","volume":"60","author":"Falsini","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/sj.bjp.0703366","article-title":"Adenosine receptor expression and function in rat striatal cholinergic interneurons","volume":"130","author":"Preston","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1126\/science.1160575","article-title":"Dichotomous dopaminergic control of striatal synaptic plasticity","volume":"321","author":"Shen","year":"2008","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1523\/JNEUROSCI.4082-10.2011","article-title":"The distinct role of medium spiny neurons and cholinergic interneurons in the D\u2082\/A\u2082A receptor interaction in the striatum: Implications for Parkinson\u2019s disease","volume":"31","author":"Tozzi","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"109329","DOI":"10.1016\/j.neuropharm.2022.109329","article-title":"Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum","volume":"223","author":"Sarasola","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Orru, M., Bake\u0161ov\u00e1, J., Brugarolas, M., Quiroz, C., Beaumont, V., Goldberg, S.R., Llu\u00eds, C., Cort\u00e9s, A., Franco, R., and Casad\u00f3, V. (2011). Striatal pre- and postsynaptic profile of adenosine A2A receptor antagonists. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016088"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.neuropharm.2014.01.045","article-title":"The P2X7 receptor antagonist Brilliant Blue G attenuates contralateral rotations in a rat model of Parkinsonism through a combined control of synaptotoxicity, neurotoxicity and gliosis","volume":"81","author":"Carmo","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1007\/s11011-017-0086-1","article-title":"Selective A2A receptor antagonist SCH 58261 modulates striatal oxidative stress and alleviates toxicity induced by 3-Nitropropionic acid in male Wistar rats","volume":"32","author":"Bortolatto","year":"2017","journal-title":"Metab. Brain Dis."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Rial, D., Castro, A.A., Machado, N., Gar\u00e7\u00e3o, P., Gon\u00e7alves, F.Q., Silva, H.B., Tom\u00e9, A.R., K\u00f6falvi, A., Corti, O., and Raisman-Vozari, R. (2014). Behavioral phenotyping of Parkin-deficient mice: Looking for early preclinical features of Parkinson\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114216"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.bbr.2015.12.011","article-title":"Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats","volume":"301","author":"Matheus","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1111\/ejn.12600","article-title":"Cellular prion protein is present in dopaminergic neurons and modulates the dopaminergic system","volume":"40","author":"Rial","year":"2014","journal-title":"Eur. J. Neurosci."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1016\/j.neurobiolaging.2008.01.003","article-title":"Modification upon aging of the density of presynaptic modulation systems in the hippocampus","volume":"30","author":"Canas","year":"2009","journal-title":"Neurobiol. Aging"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.euroneuro.2012.04.011","article-title":"Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder","volume":"23","author":"Pandolfo","year":"2013","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.neuroscience.2005.01.014","article-title":"Different synaptic and subsynaptic localization of adenosine A2A receptors in the hippocampus and striatum of the rat","volume":"132","author":"Rebola","year":"2005","journal-title":"Neuroscience"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1111\/j.1471-4159.1992.tb09420.x","article-title":"Ecto-5\u2032-nucleotidase is associated with cholinergic nerve terminals in the hippocampus but not in the cerebral cortex of the rat","volume":"59","author":"Cunha","year":"1992","journal-title":"J. Neurochem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.neurobiolaging.2007.03.025","article-title":"Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats","volume":"29","author":"Rodrigues","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4903\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:14Z","timestamp":1760107034000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":107,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094903"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094903","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}