The Critical Role of Equilibrative Nucleoside Transporter-2 in Modulating Cerebral Damage and Vascular Dysfunction in Mice with Brain Ischemia-Reperfusion.
adenosine
blood-brain barrier
equilibrative nucleoside transporters
ischemia-reperfusion injury
neuroinflammation
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
27 Jul 2023
27 Jul 2023
Historique:
received:
18
05
2023
accepted:
11
07
2023
medline:
27
7
2023
pubmed:
27
7
2023
entrez:
27
7
2023
Statut:
aheadofprint
Résumé
Cerebral vascular protection is critical for stroke treatment. Adenosine modulates vascular flow and exhibits neuroprotective effects, in which brain extracellular concentration of adenosine is dramatically increased during ischemic events and ischemia-reperfusion. Since the equilibrative nucleoside transporter-2 (Ent2) is important in regulating brain adenosine homeostasis, the present study aimed to investigate the role of Ent2 in mice with cerebral ischemia-reperfusion. Cerebral ischemia-reperfusion injury was examined in mice with transient middle cerebral artery occlusion (tMCAO) for 90 minutes, followed by 24-hour reperfusion. Infarct volume, brain edema, neuroinflammation, microvascular structure, regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO Ent2 deletion reduced the infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion. tMCAO-induced disruption of brain microvessels was ameliorated in Ent2 Ent2 plays a critical role in modulating cerebral collateral circulation and ameliorating pathological events of brain ischemia and reperfusion injury.
Sections du résumé
BACKGROUND
BACKGROUND
Cerebral vascular protection is critical for stroke treatment. Adenosine modulates vascular flow and exhibits neuroprotective effects, in which brain extracellular concentration of adenosine is dramatically increased during ischemic events and ischemia-reperfusion. Since the equilibrative nucleoside transporter-2 (Ent2) is important in regulating brain adenosine homeostasis, the present study aimed to investigate the role of Ent2 in mice with cerebral ischemia-reperfusion.
METHODS
METHODS
Cerebral ischemia-reperfusion injury was examined in mice with transient middle cerebral artery occlusion (tMCAO) for 90 minutes, followed by 24-hour reperfusion. Infarct volume, brain edema, neuroinflammation, microvascular structure, regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO
RESULTS
RESULTS
Ent2 deletion reduced the infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion. tMCAO-induced disruption of brain microvessels was ameliorated in Ent2
CONCLUSIONS
CONCLUSIONS
Ent2 plays a critical role in modulating cerebral collateral circulation and ameliorating pathological events of brain ischemia and reperfusion injury.
Identifiants
pubmed: 37498500
doi: 10.1007/s11095-023-03565-2
pii: 10.1007/s11095-023-03565-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Science and Technology Council
ID : MOST110-2320-B002-025-MY3
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, et al. Guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52:e364–467.
pubmed: 34024117
doi: 10.1161/STR.0000000000000375
Brouns R, Deyn D. The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg. 2009;111:483–95.
pubmed: 19446389
doi: 10.1016/j.clineuro.2009.04.001
Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. 2007;27:1129–38.
pubmed: 17267568
pmcid: 6673180
doi: 10.1523/JNEUROSCI.4468-06.2007
del Zoppo GJ. Inflammation and the neurovascular unit in the setting of focal cerebral ischemia. Neurosci. 2009;158:972–82.
doi: 10.1016/j.neuroscience.2008.08.028
Yu X, Ji C, Shao A. Neurovascular unit dysfunction and neurodegenerative disorders. Front Neurosci. 2020;14:334.
pubmed: 32410936
pmcid: 7201055
doi: 10.3389/fnins.2020.00334
Krueger M, Mages B, Hobusch C, Michalski D. Endothelial edema precedes blood-brain barrier breakdown in early time points after experimental focal cerebral ischemia. Acta Neuropathol Commun. 2019;7:17.
pubmed: 30744693
pmcid: 6369548
doi: 10.1186/s40478-019-0671-0
Ganesana M, Venton BJ. Early changes in transient adenosine during cerebral ischemia and reperfusion injury. PLoS One. 2018;13:e0196932.
pubmed: 29799858
pmcid: 5969733
doi: 10.1371/journal.pone.0196932
Kitagawa H, Mori A, Shimada J, Mitsumoto Y, Kikuchi T. Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats. Neurol Res. 2002;24:317–23.
pubmed: 11958429
doi: 10.1179/016164102101199819
Seydyousefi M, Moghanlou AE, Metz GAS, Gursoy R, Faghfoori MH, Mirghani SJ, et al. Exogenous adenosine facilitates neuroprotection and functional recovery following cerebral ischemia in rats. Brain Res Bull. 2019;153:250–6.
pubmed: 31545998
doi: 10.1016/j.brainresbull.2019.09.010
Yao SY, Ng AM, Vickers MF, Sundaram M, Cass CE, Baldwin SA, et al. Functional and molecular characterization of nucleobase transport by recombinant human and rat equilibrative nucleoside transporters 1 and 2. Chimeric constructs reveal a role for the ENT2 helix 5-6 region in nucleobase translocation. J Biol Chem. 2002;277:24938–48.
pubmed: 12006583
doi: 10.1074/jbc.M200966200
Wu KC, Lee CY, Chou FY, Chern Y, Lin CJ. Deletion of equilibrative nucleoside transporter-2 protects against lipopolysaccharide-induced neuroinflammation and blood-brain barrier dysfunction in mice. Brain Behav Immun. 2020;84:59–71.
pubmed: 31751618
doi: 10.1016/j.bbi.2019.11.008
Nagai K, Nagasawa K, Fujimoto S. Transport mechanisms for adenosine and uridine in primary-cultured rat cortical neurons and astrocytes. Biochem Biophys Res Commun. 2005;334:1343–50.
pubmed: 16043124
doi: 10.1016/j.bbrc.2005.07.032
Wu KC, Lee CY, Chern Y, Lin CJ. Amelioration of lipopolysaccharide-induced memory impairment in equilibrative nucleoside transporter-2 knockout mice is accompanied by the changes in glutamatergic pathways. Brain Behav Immun. 2021;96:187–99.
pubmed: 34058310
doi: 10.1016/j.bbi.2021.05.027
Liu YC, Tsai YH, Tang SC, Liou HC, Kang KH, Liou HH, et al. Cytokine MIF enhances blood-brain barrier permeability: impact for therapy in ischemic stroke. Sci Rep. 2018;8:743.
pubmed: 29335619
pmcid: 5768806
doi: 10.1038/s41598-017-16927-9
Popoli P, Pintor A, Domenici MR, Frank C, Tebano MT, Pèzzola A, et al. Blockade of striatal adenosine A
pubmed: 11880527
pmcid: 6758877
doi: 10.1523/JNEUROSCI.22-05-01967.2002
Muto J, Lee H, Lee H, Uwaya A, Park J, Nakajima S, et al. Oral administration of inosine produces anti-depressant-like effects in mice. Sci Rep. 2014;4:4199.
pubmed: 24569499
pmcid: 3935199
doi: 10.1038/srep04199
Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, et al. Inhibition of interleukin-1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A. 1997;94:2007–12.
pubmed: 9050895
pmcid: 20033
doi: 10.1073/pnas.94.5.2007
Broughton BRS, Brait VH, Guida E, Lee S, Arumugam TV, Gardiner-Mann CV, et al. Stroke increases G protein-coupled estrogen receptor expression in the brain of male but not female mice. Neurosignals. 2013;21:229–39.
pubmed: 22869326
doi: 10.1159/000338019
Wang HL, Chen JW, Yang SH, Lo YC, Pan HC, Liang YW, et al. Multimodal optical imaging to investigate spatiotemporal changes in cerebrovascular function in AUDA treatment of acute ischemic stroke. Front Cell Neurosci. 2021;15:655305.
pubmed: 34149359
pmcid: 8209306
doi: 10.3389/fncel.2021.655305
Ju TC, Chen HM, Chen YC, Chang CP, Chang C, Chern Y. AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease. Biochim Biophys Acta. 2014;1842:1668–80.
pubmed: 24946181
doi: 10.1016/j.bbadis.2014.06.012
McColl BW, Rothwell NJ, Allan SM. Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1 and neutrophil-dependent mechanisms. J Neurosci. 2007;27:4403–12.
pubmed: 17442825
pmcid: 6672305
doi: 10.1523/JNEUROSCI.5376-06.2007
Vidale S, Consoli A, Arnaboldi M, Consoli D. Postischemic inflammation in acute stroke. J Clin Neurol. 2017;13:1–9.
pubmed: 28079313
doi: 10.3988/jcn.2017.13.1.1
McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci. 2008;28:9451–62.
pubmed: 18799677
pmcid: 6671112
doi: 10.1523/JNEUROSCI.2674-08.2008
Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron. 2014;82:603–17.
pubmed: 24746419
pmcid: 4016169
doi: 10.1016/j.neuron.2014.03.003
Nicchia GP, Nico B, Camassa LM, Mola MG, Loh N, Dermietzel R, et al. The role of aquaporin-4 in the blood-brain barrier development and integrity: studies in animal and cell culture models. Neurosci. 2004;129:935–45.
doi: 10.1016/j.neuroscience.2004.07.055
Zhang D, Jin W, Liu H, Liang T, Peng Y, Zhang J, et al. ENT1 inhibition attenuates apoptosis by activation of cAMP/pCREB/Bcl2 pathway after MCAO in rats. Exp Neurol. 2020;331:113362.
pubmed: 32445645
doi: 10.1016/j.expneurol.2020.113362
Wang CX, Shuaib A. Critical role of microvasculature basal lamina in ischemic brain injury. Prog Neurobiol. 2007;83:140–8.
pubmed: 17868971
doi: 10.1016/j.pneurobio.2007.07.006
Morancho A, Rosell A, García-Bonilla L, Montaner J. Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? Ann N Y Acad Sci. 2010;1207:123–33.
pubmed: 20955435
doi: 10.1111/j.1749-6632.2010.05734.x
Montaner J, Alvarez-Sabín J, Molina CA, Anglés A, Abilleira S, Arenillas J, et al. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke. 2001;32:2762–7.
pubmed: 11739970
doi: 10.1161/hs1201.99512
Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000;20:1681–9.
pubmed: 11129784
doi: 10.1097/00004647-200012000-00007
Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011;42:3323–8.
pubmed: 21940972
pmcid: 3584169
doi: 10.1161/STROKEAHA.110.608257
Tsuji K, Aoki T, Tejima E, Arai K, Lee SR, Atochin DN, et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke. 2005;36:1954–9.
pubmed: 16051896
doi: 10.1161/01.STR.0000177517.01203.eb
Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European stroke prevention study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13.
pubmed: 8981292
doi: 10.1016/S0022-510X(96)00308-5
Leonardi-Bee BPMW, Bousser M, Davalos A, Diener H, Guiraud-Chaumeil B, et al. Dipyridamole for preventing recurrent ischemic stroke and other vascular events: a meta-analysis of individual patient data from randomized controlled trials. Stroke. 2005;36:162–8.
pubmed: 15569877
doi: 10.1161/01.STR.0000149621.95215.ea
Kunz W, Mueller E, Siess M. The distribution of dipyridamole in the body and in the myocardial cell of rats and mice. Arzneim Forsch. 1963;13:179–85.
Sun C, Lin L, Yin L, Hao X, Tian J, Zhang X, et al. Acutely inhibiting AQP4 with TGN-020 improves functional outcome by attenuating edema and peri-infarct astrogliosis after cerebral ischemia. Front Immunol. 2022;13:870029.
pubmed: 35592320
pmcid: 9110854
doi: 10.3389/fimmu.2022.870029
Hirt L, Fukuda AM, Ambadipudi K, Rashid F, Binder D, Verkman A, et al. Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. J Cereb Blood Flow Metab. 2017;37:277–90.
pubmed: 26767580
doi: 10.1177/0271678X15623290
Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6:159–63.
pubmed: 10655103
doi: 10.1038/72256
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS. Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. Lancet Neurol. 2011;10:909–21.
pubmed: 21939900
doi: 10.1016/S1474-4422(11)70195-8
Kondo T, Reaume AG, Huang TT, Carlson E, Murakami K, Chen SF, et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci. 1997;17:4180–9.
pubmed: 9151735
pmcid: 6573543
doi: 10.1523/JNEUROSCI.17-11-04180.1997
Peters O, Back T, Lindauer U, Busch C, Megow D, Dreier J, et al. Increased formation of reactive oxygen species after permanent and reversible middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1998;18:196–205.
pubmed: 9469163
doi: 10.1097/00004647-199802000-00011
Yamato M, Egashira T, Utsumi H. Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke. Free Radic Biol Med. 2003;35:1619–31.
pubmed: 14680685
doi: 10.1016/j.freeradbiomed.2003.09.013
Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci. 2004;5:347–60.
pubmed: 15100718
doi: 10.1038/nrn1387
Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry. 2004;75:353–61.
pubmed: 14966145
pmcid: 1738983
doi: 10.1136/jnnp.2003.025825
Fan JL, Brassard P, Rickards CA, Nogueira RC, Nasr N, McBryde FD, Fisher JP, Tzeng YC. Integrative cerebral blood flow regulation in ischemic stroke. J Cereb Blood Flow Metab. 2022;42:387–403.
pubmed: 34259070
doi: 10.1177/0271678X211032029
Hegedüs K, Keresztes T, Fekete I, Molnár L. Effect of i.v. Dipyridamole on cerebral blood flow, blood pressure, plasma adenosine and cAMP levels in rabbits. J Neurol Sci. 1997;148:153–61.
pubmed: 9129111
doi: 10.1016/S0022-510X(96)05352-X
Klaasse EC, Ijzerman AP, de Grip WJ, Beukers MW. Internalization and desensitization of adenosine receptors. Purinergic Signal. 2008;4:21–37.
pubmed: 18368531
doi: 10.1007/s11302-007-9086-7
Pedata F, Pugliese AM, Coppi E, Dettori I, Maraula G, Cellai L, et al. Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia. Mediat Inflamm. 2014;2014:805198.
doi: 10.1155/2014/805198
Ernens I, Rouy D, Velot E, Devaux Y, Wagner DR. Adenosine inhibits matrix metalloproteinase-9 secretion by neutrophils: implication of A
pubmed: 16917093
doi: 10.1161/01.RES.0000241428.82502.d4
Ngai AC, Coyne EF, Meno JR, West GA, Winn HR. Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles. Am J Physio Heart Circ Physiol. 2001;280:H2329–35.
doi: 10.1152/ajpheart.2001.280.5.H2329
Shen H, Chen GJ, Harvey BK, Bickford PC, Wang Y. Inosine reduces ischemic brain injury in rats. Stroke. 2005;36:654–9.
pubmed: 15692110
doi: 10.1161/01.STR.0000155747.15679.04
Welihinda AA, Kaur M, Greene K, Zhai Y, Amento EP. The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias. Cell Signal. 2016;28:552–60.
pubmed: 26903141
pmcid: 4826793
doi: 10.1016/j.cellsig.2016.02.010
Smith KM, Ng AML, Yao SYM, Labedz KA, Knaus EE, Wiebe LI, Cass CE, Baldwin SA, Chen XZ, Karpinski E, Young JD. Electrophysiological characterization of a recombinant human Na+−coupled nucleoside transporter (hCNT1) produced in Xenopus oocytes. J Physiol. 2004;558:807–23.
pubmed: 15194733
pmcid: 1665023
doi: 10.1113/jphysiol.2004.068189
Pastor-Anglada M, Pérez-Torras S. Emerging roles of nucleoside transporters. Front Pharmacol. 2018;9:606.
pubmed: 29928232
pmcid: 5997781
doi: 10.3389/fphar.2018.00606
Parkinson FE, Damaraju VL, Graham K, Yao SYM, Baldwin SA, Cass CE, Young JD. Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr Top Med Chem. 2011;11:948–72.
pubmed: 21401500
doi: 10.2174/156802611795347582
Medina-Pulido L, Molina-Arcas M, Justicia C, Soriano E, Burgaya F, Planas AM, Pastor-Anglada M. Hypoxia and P1 receptor activation regulate the high-affinity concentrative adenosine transporter CNT2 in differentiated neuronal PC12 cells. Biochem J. 2013;545:437–45.
doi: 10.1042/BJ20130231