Abstract
Evidence indicates that the adenosine A2A receptor subtype is of critical importance in stroke. In previous studies, in the model of permanent middle cerebral artery occlusion (pMCAo), the adenosine A2A receptor antagonist, SCH58261, administered soon after ischemia, proved protective against excessive glutamate outflow in the first 4 h after ischemia and against neurological deficit and tissue damage evaluated 24 h after pMCAo. In the present work, we investigated if neuroprotective effect of SCH58261 was maintained 7 days after transient MCAo (tMCAo). SCH58261 (0.01 mg/kg, i.p.), administered twice/day for 7 days, protected from neurological deficit 1 day after tMCAo, but no more after 5 and 7 days. Two days after tMCAo, SCH58261 did not reduce blood cell infiltration, evaluated as HIS-48 positive cells, into ischemic striatal and cortical tissue. Moreover, 7 days after tMCAo, SCH58261 has not protected ischemic areas from damage and has not ameliorated myelin organization into the ischemic striatum. Protection by the A2A receptor antagonist 24 h after ischemia is attributable to reduced excitotoxicity. Seven days after ischemia the early protective effect of the A2A receptor antagonist likely has been overwhelmed by a secondary damage due to blood cell infiltration and neuroinflammation.
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References
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397
Gui L, Duan W, Tian H, Li C, Zhu J, Chen JF, Zheng J (2009) Adenosine A2A receptor deficiency reduces striatal glutamate outflow and attenuates brain injury induced by transient focal cerebral ischemia in mice. Brain Res 1297:185–193
Melani A, Pantoni L, Bordoni F, Gianfriddo M, Bianchi L, Vannucchi MG, Bertorelli R, Monopoli A, Pedata F (2003) The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Res 959(2):243–250
Phillis JW, Smith-Barbour M, O’Regan MH, Perkins LM (1994) Amino acid and purine release in rat brain following temporary middle cerebral artery occlusion. Neurochem Res 19(9):1125–1130
Shirotani T, Shima K, Chigasaki H (1995) In vivo studies of extracellular metabolites in the striatum after distal middle cerebral artery occlusion in stroke-prone spontaneously hypertensive rats. Stroke 26(5):878–884
Matsumoto K, Graf R, Rosner G, Shimada N, Heiss WD (1992) Flow thresholds for extracellular purine catabolite elevation in cat focal ischemia. Brain Res 579(2):309–314
Melani A, Pantoni L, Corsi C, Bianchi L, Monopoli A, Bertorelli R, Pepeu G, Pedata F (1999) Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage. Stroke 30(11):2448–2454
Melani A, Corti F, Stephan H, Müller CE, Donati C, Bruni P, Vannucchi MG, Pedata F (2012) Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum. Exp Neurol 233(1):193–204
Phillis JW, Smith-Barbour M, O’Regan MH (1996) Changes in extracellular amino acid neurotransmitters and purines during and following ischemias of different durations in the rat cerebral cortex. Neurochem Int 29(2):115–120
Chen JF, Sonsalla P, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multi-faced actions and “fine tuning” modulation. Prog Neurobiol 83(5):310–331
Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14(15):1490–1499
Pedata F, Pugliese AM, Coppi E, Dettori I, Maraula G, Cellai L, Melani A (2014) Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia. Mediators Inflamm 2014:805198
Fink JS, Weaver DR, Rivkees SA, Peterfreund RA, Pollack AE, Adler EM, Reppert SM (1992) Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Brain Res Mol Brain Res 14(3):186–195
Schiffmann SN, Libert F, Vassart G, Vanderhaeghen JJ (1991) Distribution of adenosine A2 receptor mRNA in the human brain. Neurosci Lett 130(2):177–181
Fiebich BL, Biber K, Lieb K, van Calker D, Berger M, Bauer J, Gebicke-Haerter PJ (1996) Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2A-receptors. Glia. 18(2):152–160
Stevens B, Porta S, Haak LL, Gallo V, Fields RD (2002) Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials. Neuron 36(5):855–868
Lee YC, Chien CL, Sun CN, Huang CL, Huang NK, Chiang MC, Lai HL, Lin YS, Chou SY, Wang CK, Tai MH, Liao WL, Lin TN, Liu FC, Chern Y (2003) Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur J Neurosci 18(7):1786–1796
Antonioli L, Csóka B, Fornai M, Colucci R, Kókai E, Blandizzi C, Haskó G (2014) Adenosine and inflammation: what’s new on the horizon? Drug Discov Today 19(8):1051–1068
Haskó G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7(9):759–770
Trincavelli ML, Melani A, Guidi S, Cuboni S, Cipriani S, Pedata F, Martini C (2008) Regulation of A(2A) adenosine receptor expression and functioning following permanent focal ischemia in rat brain. J Neurochem 104(2):479–490
Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E (1998) Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport 9(17):3955–3959
Melani A, Gianfriddo M, Vannucchi MG, Cipriani S, Baraldi PG, Giovannini MG, Pedata F (2006) The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia. Brain Res 1073–1074:470–480
Melani A, Cipriani S, Vannucchi MG, Nosi D, Donati C, Bruni P, Giovannini MG, Pedata F (2009) Selective adenosine A2A receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia. Brain 132(Pt 6):1480–1495
Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, Moskowitz MA, Fink JS, Schwarzschild MA (1999) A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci 19(21):9192–9200
Liu S, Zhen G, Meloni BP, Campbell K, Winn HR (2009) Rodent stroke model guidelines for preclinical stroke trials (1st edition). J Exp Stroke Transl Med 2(2):2–27
Detante O, Jaillard A, Moisan A, Barbieux M, Favre IM, Garambois K, Hommel M, Remy C (2014) Biotherapies in stroke. Rev Neurol (Paris) 170(12):779–798
Melani A, Corti F, Cellai L, Vannucchi MG, Pedata F (2014) Low doses of the selective adenosine A2A receptor agonist CGS21680 are protective in a rat model of transient cerebral ischemia. Brain Res 1551:59–72
Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez-Ramos J, Chopp M (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32(11):2682–2688
Konig JFR, Klippel RA (1967) The rat atlas: a stereotaxic atlas of the forebrain and lower parts of the brain stem. Williams and Wilkins, Baltimore
Rousselet E, Kriz J, Seidah NG (2012) Mouse model of intraluminal MCAO: cerebral infarct evaluation by cresyl violet staining. J Vis Exp 69:4038
Danner H, Pfister C (1981) The cytoarchitecture of the rat globus pallidus. J Hirnforsch 22:47–57
Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe CU, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40(5):1849–1857
Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66(3):232–245
Stoll G, Jander S, Schroeter M (1998) Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 56(2):149–171
Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17(7):796–808
Pantoni L, Sarti C, Inzitari D (1998) Cytokines and cell adhesion molecules in cerebral ischemia: experimental bases and therapeutic perspectives. Arterioscler Thromb Vasc Biol 18(4):503–513
del Zoppo GJ (2009) Relationship of neurovascular elements to neuron injury during ischemia. Cerebrovasc Dis 27(Suppl 1):65–76
Dirnagl U (2012) Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci 1268:21–25
Zhang RL, Chopp M, Chen H, Garcia JH (1994) Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurol Sci 125(1):3–10
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This investigation was supported by funding obtained from the Italian Ministry of University and Research (MIUR) and from the University of Florence.
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Melani, A., Dettori, I., Corti, F. et al. Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia. Neurol Sci 36, 1441–1448 (2015). https://doi.org/10.1007/s10072-015-2160-y
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DOI: https://doi.org/10.1007/s10072-015-2160-y