Skip to main content
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 May 3;29(3):390–398. doi: 10.1007/s12264-013-1338-7

P2X7 receptors in cerebral ischemia

Hui-Yu Bai 1, Ai-Ping Li 1,
PMCID: PMC5561845  PMID: 23640286

Abstract

Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people. It leads immediately to rapid energy failure, ATP depletion, and ionic imbalance, which increase extracellular ATP levels and accordingly activate P2X7 receptors. These receptors are ATP-gated cation channels and widely distributed in nerve cells, especially in the immunocompetent cells of the brain. Currently, interest in the roles of P2X7 receptors in ischemic brain injury is growing. In this review, we discuss recent research progress on the actions of P2X7 receptors, their possible mechanisms in cerebral ischemia, and the potential therapeutic value of P2X7 receptor antagonists which may provide a new target both for clinical and for research purposes.

Keywords: P2X7 receptor, cerebral ischemia, neurotoxicity, calcium overload, neuroinflammation, neurotransmitter, receptor antagonist

References

  • [1].Franke H, Gunther A, Grosche J, Schmidt R, Rossner S, Reinhardt R, et al. P2X7 receptor expression after ischemia in the cerebral cortex of rats. J Neuropathol Exp Neurol. 2004;63:686–699. doi: 10.1093/jnen/63.7.686. [DOI] [PubMed] [Google Scholar]
  • [2].Fields RD, Burnstock G. Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci. 2006;7:423–436. doi: 10.1038/nrn1928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Sperlagh B, Vizi ES, Wirkner K, Illes P. P2X7 receptors in the nervous system. Prog Neurobiol. 2006;78:327–346. doi: 10.1016/j.pneurobio.2006.03.007. [DOI] [PubMed] [Google Scholar]
  • [4].Melani A, Amadio S, Gianfriddo M, Vannucchi MG, Volonte C, Bernardi G, et al. P2X7 receptor modulation on microglial cells and reduction of brain infarct caused by middle cerebral artery occlusion in rat. J Cereb Blood Flow Metab. 2006;26:974–982. doi: 10.1038/sj.jcbfm.9600250. [DOI] [PubMed] [Google Scholar]
  • [5].North RA. Molecular physiology of P2X receptors. Physiol Rev. 2002;82:1013–1067. doi: 10.1152/physrev.00015.2002. [DOI] [PubMed] [Google Scholar]
  • [6].Surprenant A, North RA. Signaling at purinergic P2X receptors. Annu Rev Physiol. 2009;71:333–359. doi: 10.1146/annurev.physiol.70.113006.100630. [DOI] [PubMed] [Google Scholar]
  • [7].Takenouchi T, Sekiyama K, Sekigawa A, Fujita M, Waragai M, Sugama S, et al. P2X7 receptor signaling pathway as a therapeutic target for neurodegenerative diseases. Arch Immunol Ther Exp (Warsz) 2010;58:91–96. doi: 10.1007/s00005-010-0069-y. [DOI] [PubMed] [Google Scholar]
  • [8].Skaper SD, Debetto P G P. The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB J. 2010;24:337–345. doi: 10.1096/fj.09-138883. [DOI] [PubMed] [Google Scholar]
  • [9].Arbeloa J, Perez-Samartin A, Gottlieb M, Matute C. P2X7 receptor blockade prevents ATP excitotoxicity in neurons and reduces brain damage after ischemia. Neurobiol Dis. 2012;45:954–961. doi: 10.1016/j.nbd.2011.12.014. [DOI] [PubMed] [Google Scholar]
  • [10].Friedle SA, Curet MA, Watters JJ. Recent patents on novel P2X(7) receptor antagonists and their potential for reducing central nervous system inflammation. Recent Pat CNS Drug Discov. 2010;5:35–45. doi: 10.2174/157488910789753530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Cavaliere F, Amadio S, Sancesario G, Bernardi G, Volonte C. Synaptic P2X7 and oxygen/glucose deprivation in organotypic hippocampal cultures. J Cereb Blood Flow Metab. 2004;24:392–398. doi: 10.1097/00004647-200404000-00004. [DOI] [PubMed] [Google Scholar]
  • [12].Le Feuvre RA, Brough D, Touzani O, Rothwell NJ. Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivo. J Cereb Blood Flow Metab. 2003;23:381–384. doi: 10.1097/00004647-200303000-00013. [DOI] [PubMed] [Google Scholar]
  • [13].Yanagisawa D, Kitamura Y, Takata K, Hide I, Nakata Y, Taniguchi T. Possible involvement of P2X7 receptor activation in microglial neuroprotection against focal cerebral ischemia in rats. Biol Pharm Bull. 2008;31:1121–1130. doi: 10.1248/bpb.31.1121. [DOI] [PubMed] [Google Scholar]
  • [14].Wang LY, Cai WQ, Chen PH, Deng QY, Zhao CM. Downregulation of P2X7 receptor expression in rat oligodendrocyte precursor cells after hypoxia ischemia. Glia. 2009;57:307–319. doi: 10.1002/glia.20758. [DOI] [PubMed] [Google Scholar]
  • [15].Virginio C, MacKenzie A, North RA, Surprenant A. Kinetics of cell lysis, dye uptake and permeability changes in cells expressing the rat P2X7 receptor. J Physiol. 1999;519(Pt2):335–346. doi: 10.1111/j.1469-7793.1999.0335m.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Monif M, Burnstock G, Williams DA. Microglia: proliferation and activation driven by the P2X7 receptor. Int J Biochem Cell Biol. 2010;42:1753–1756. doi: 10.1016/j.biocel.2010.06.021. [DOI] [PubMed] [Google Scholar]
  • [17].Adinolfi E, Pizzirani C, Idzko M, Panther E, Norgauer J, Di Virgilio F, et al. P2X(7) receptor: Death or life? Purinergic Signal. 2005;1:219–227. doi: 10.1007/s11302-005-6322-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Anderson CM, Nedergaard M. Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci. 2006;29:257–262. doi: 10.1016/j.tins.2006.03.003. [DOI] [PubMed] [Google Scholar]
  • [19].Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Seguela P, et al. International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits. Pharmacol Rev. 2001;53:107–118. [PubMed] [Google Scholar]
  • [20].Monif M, Reid CA, Powell KL, Smart ML, Williams DA. The P2X7 receptor drives microglial activation and proliferation: a trophic role for P2X7R pore. J Neurosci. 2009;29:3781–3791. doi: 10.1523/JNEUROSCI.5512-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Wirkner K, Kofalvi A, Fischer W, Gunther A, Franke H, Groger-Arndt H, et al. Supersensitivity of P2X receptors in cerebrocortical cell cultures after in vitro ischemia. J Neurochem. 2005;95:1421–1437. doi: 10.1111/j.1471-4159.2005.03465.x. [DOI] [PubMed] [Google Scholar]
  • [22].Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med. 2004;10:821–827. doi: 10.1038/nm1082. [DOI] [PubMed] [Google Scholar]
  • [23].Melani A, Turchi D, Vannucchi MG, Cipriani S, Gianfriddo M, Pedata F. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int. 2005;47:442–448. doi: 10.1016/j.neuint.2005.05.014. [DOI] [PubMed] [Google Scholar]
  • [24].Le Feuvre R, Brough D, Rothwell N. Extracellular ATP and P2X7 receptors in neurodegeneration. Eur J Pharmacol. 2002;447:261–269. doi: 10.1016/S0014-2999(02)01848-4. [DOI] [PubMed] [Google Scholar]
  • [25].Milius D, Sperlagh B, Illes P. Up-regulation of P2X7 receptorimmunoreactivity by in vitro ischemia on the plasma membrane of cultured rat cortical neurons. Neurosci Lett. 2008;446:45–50. doi: 10.1016/j.neulet.2008.09.023. [DOI] [PubMed] [Google Scholar]
  • [26].Duan S, Anderson CM, Keung EC, Chen Y, Swanson RA. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci. 2003;23:1320–1328. doi: 10.1523/JNEUROSCI.23-04-01320.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Zeng W, Tong Y, Li H, Luo R, Mao M. P2X7 receptor modulation of the viability of radial glial clone L2.3 cells during hypoxic-ischemic brain injury. Mol Med Report. 2012;5:1357–1361. doi: 10.3892/mmr.2012.816. [DOI] [PubMed] [Google Scholar]
  • [28].Nakanishi M, Mori T, Nishikawa K, Sawada M, Kuno M, Asada A. The effects of general anesthetics on P2X7 and P2Y receptors in a rat microglial cell line. Anesth Analg. 2007;104:1136–1144. doi: 10.1213/01.ane.0000260615.12553.4e. [DOI] [PubMed] [Google Scholar]
  • [29].Takenouchi T, Iwamaru Y, Sugama S, Sato M, Hashimoto M, Kitani H. Lysophospholipids and ATP mutually suppress maturation and release of IL-1 beta in mouse microglial cells using a Rho-dependent pathway. J Immunol. 2008;180:7827–7839. doi: 10.4049/jimmunol.180.12.7827. [DOI] [PubMed] [Google Scholar]
  • [30].Yu Y, Ugawa S, Ueda T, Ishida Y, Inoue K, Kyaw Nyunt A, et al. Cellular localization of P2X7 receptor mRNA in the rat brain. Brain Res. 2008;1194:45–55. doi: 10.1016/j.brainres.2007.11.064. [DOI] [PubMed] [Google Scholar]
  • [31].Atkinson L, Milligan CJ, Buckley NJ, Deuchars J. An ATPgated ion channel at the cell nucleus. Nature. 2002;420:42. doi: 10.1038/420042a. [DOI] [PubMed] [Google Scholar]
  • [32].Frizzo JK, Cardoso MP, de Assis AM, Perry ML, Volonte C, Frizzo ME. Effects of acute perinatal asphyxia in the rat hippocampus. Cell Mol Neurobiol. 2010;30:683–692. doi: 10.1007/s10571-009-9492-1. [DOI] [PubMed] [Google Scholar]
  • [33].Lee M, Lee SJ, Choi HJ, Jung YW, Frokiaer J, Nielsen S, et al. Regulation of AQP4 protein expression in rat brain astrocytes: role of P2X7 receptor activation. Brain Res. 2008;1195:1–11. doi: 10.1016/j.brainres.2007.12.023. [DOI] [PubMed] [Google Scholar]
  • [34].Cavaliere F, Dinkel K, Reymann K. Microglia response and P2 receptor participation in oxygen/glucose deprivation-induced cortical damage. Neuroscience. 2005;136:615–623. doi: 10.1016/j.neuroscience.2005.04.038. [DOI] [PubMed] [Google Scholar]
  • [35].Cavaliere F, D’Ambrosi N, Ciotti MT, Mancino G, Sancesario G, Bernardi G, et al. Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists. Neurochem Int. 2001;38:189–197. doi: 10.1016/S0197-0186(00)00088-7. [DOI] [PubMed] [Google Scholar]
  • [36].Skaper SD. Ion channels on microglia: therapeutic targets for neuroprotection. CNS Neurol Disord Drug Targets. 2011;10:44–56. doi: 10.2174/187152711794488638. [DOI] [PubMed] [Google Scholar]
  • [37].Boucsein C, Zacharias R, Farber K, Pavlovic S, Hanisch UK, Kettenmann H. Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. Eur J Neurosci. 2003;17:2267–2276. doi: 10.1046/j.1460-9568.2003.02663.x. [DOI] [PubMed] [Google Scholar]
  • [38].Pellegatti P, Falzoni S, Pinton P, Rizzuto R, Di Virgilio F. A novel recombinant plasma membrane-targeted luciferase reveals a new pathway for ATP secretion. Mol Biol Cell. 2005;16:3659–3665. doi: 10.1091/mbc.E05-03-0222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Browne LE, Jiang LH, North RA. New structure enlivens interest in P2X receptors. Trends Pharmacol Sci. 2010;31:229–237. doi: 10.1016/j.tips.2010.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Kharlamov A, Jones SC, Kim DK. Suramin reduces infarct volume in a model of focal brain ischemia in rats. Exp Brain Res. 2002;147:353–359. doi: 10.1007/s00221-002-1251-1. [DOI] [PubMed] [Google Scholar]
  • [41].Cavaliere F, Amadio S, Dinkel K, Reymann KG, Volonte C. P2 receptor antagonist trinitrophenyl-adenosine-triphosphate protects hippocampus from oxygen and glucose deprivation cell death. J Pharmacol Exp Ther. 2007;323:70–77. doi: 10.1124/jpet.106.119024. [DOI] [PubMed] [Google Scholar]
  • [42].Sperlagh B, Zsilla G, Baranyi M, Illes P, Vizi ES. Purinergic modulation of glutamate release under ischemic-like conditions in the hippocampus. Neuroscience. 2007;149:99–111. doi: 10.1016/j.neuroscience.2007.07.035. [DOI] [PubMed] [Google Scholar]
  • [43].Runden-Pran E, Tanso R, Haug FM, Ottersen OP, Ring A. Neuroprotective effects of inhibiting N-methyl-D-aspartate receptors, P2X receptors and the mitogen-activated protein kinase cascade: a quantitative analysis in organotypical hippocampal slice cultures subjected to oxygen and glucose deprivation. Neuroscience. 2005;136:795–810. doi: 10.1016/j.neuroscience.2005.08.069. [DOI] [PubMed] [Google Scholar]
  • [44].Bano D, Nicotera P. Ca2+ signals and neuronal death in brain ischemia. Stroke. 2007;38:674–676. doi: 10.1161/01.STR.0000256294.46009.29. [DOI] [PubMed] [Google Scholar]
  • [45].Csordas G, Hajnoczky G. SR/ER-mitochondrial local communication: calcium and ROS. Biochim Biophys Acta. 2009;1787:1352–1362. doi: 10.1016/j.bbabio.2009.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Iwabuchi S, Kawahara K. Functional significance of the negative-feedback regulation of ATP release via pannexin-1 hemichannels under ischemic stress in astrocytes. Neurochem Int. 2011;58:376–384. doi: 10.1016/j.neuint.2010.12.013. [DOI] [PubMed] [Google Scholar]
  • [47].Lu YM, Tao RR, Huang JY, Li LT, Liao MH, Li XM, et al. P2X7 signaling promotes microsphere embolism-triggered microglia activation by maintaining elevation of Fas ligand. J Neuroinflammation. 2012;9:172. doi: 10.1186/1742-2094-9-172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Faustino JV, Wang X, Johnson CE, Klibanov A, Derugin N, Wendland MF, et al. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci. 2011;31:12992–13001. doi: 10.1523/JNEUROSCI.2102-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Skaper SD, Facci L, Culbert AA, Evans NA, Chessell I, Davis JB, et al. P2X(7) receptors on microglial cells mediate injury to cortical neurons in vitro. Glia. 2006;54:234–242. doi: 10.1002/glia.20379. [DOI] [PubMed] [Google Scholar]
  • [50].Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y. Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci. 2004;24:1–7. doi: 10.1523/JNEUROSCI.3792-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Chu K, Yin B, Wang J, Peng G, Liang H, Xu Z, et al. Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus. J Neuroinflammation. 2012;9:69. doi: 10.1186/1742-2094-9-69. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Takenouchi T, Iwamaru Y, Sugama S, Tsukimoto M, Fujita M, Sekigawa A, et al. The activation of P2X7 receptor induces cathepsin D-dependent production of a 20-kDa form of IL-1beta under acidic extracellular pH in LPS-primed microglial cells. J Neurochem. 2011;117:712–723. doi: 10.1111/j.1471-4159.2011.07240.x. [DOI] [PubMed] [Google Scholar]
  • [53].Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–550. doi: 10.1146/annurev.immunol.021908.132612. [DOI] [PubMed] [Google Scholar]
  • [54].Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, et al. Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol. 2005;174:7268–7277. doi: 10.4049/jimmunol.174.11.7268. [DOI] [PubMed] [Google Scholar]
  • [55].Takenouchi T, Fujita M, Sugama S, Kitani H, Hashimoto M. The role of the P2X7 receptor signaling pathway for the release of autolysosomes in microglial cells. Autophagy. 2009;5:723–724. doi: 10.4161/auto.5.5.8478. [DOI] [PubMed] [Google Scholar]
  • [56].Sperlagh B, Kofalvi A, Deuchars J, Atkinson L, Milligan CJ, Buckley NJ, et al. Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus. J Neurochem. 2002;81:1196–1211. doi: 10.1046/j.1471-4159.2002.00920.x. [DOI] [PubMed] [Google Scholar]
  • [57].Lo JC, Huang WC, Chou YC, Tseng CH, Lee WL, Sun SH. Activation of P2X(7) receptors decreases glutamate uptake and glutamine synthetase activity in RBA-2 astrocytes via distinct mechanisms. J Neurochem. 2008;105:151–164. doi: 10.1111/j.1471-4159.2007.05119.x. [DOI] [PubMed] [Google Scholar]
  • [58].Matute C. Glutamate and ATP signalling in white matter pathology. J Anat. 2011;219:53–64. doi: 10.1111/j.1469-7580.2010.01339.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [59].Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: an overview. Trends Neurosci. 2009;32:19–29. doi: 10.1016/j.tins.2008.10.001. [DOI] [PubMed] [Google Scholar]
  • [60].Beigi RD, Kertesy SB, Aquilina G, Dubyak GR. Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms. Br J Pharmacol. 2003;140:507–519. doi: 10.1038/sj.bjp.0705470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Sikora A, Liu J, Brosnan C, Buell G, Chessel I, Bloom BR. Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism. J Immunol. 1999;163:558–561. [PubMed] [Google Scholar]
  • [62].Choi HB, Ryu JK, Kim SU, McLarnon JG. Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. J Neurosci. 2007;27:4957–4968. doi: 10.1523/JNEUROSCI.5417-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Yan XB, Meng FJ, Song B, Zhang GY. Brain ischemia induces serine phosphorylation of neuronal nitric oxide synthase by Ca(2+)/calmodulin-dependent protein kinase II in rat hippocampus. Acta Pharmacol Sin. 2004;25:617–622. [PubMed] [Google Scholar]
  • [64].Alloisio S, Cervetto C, Passalacqua M, Barbieri R, Maura G, Nobile M, et al. Functional evidence for presynaptic P2X7 receptors in adult rat cerebrocortical nerve terminals. FEBS Lett. 2008;582:3948–3953. doi: 10.1016/j.febslet.2008.10.041. [DOI] [PubMed] [Google Scholar]
  • [65].Zhang Y, Deng P, Li Y, Xu ZC. Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia. J Neurophysiol. 2006;95:1537–1544. doi: 10.1152/jn.01166.2005. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES