Skip to main content

Advertisement

SpringerLink
Log in

Exogenous Adenosine Antagonizes Excitatory Amino Acid Toxicity in Primary Astrocytes

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Excitatory toxicity is still a hot topic in the study of ischemic stroke, and related research has focused mainly on neurons. Adenosine is an important neuromodulator that is known as a “biosignature” in the central nervous system (CNS). The protective effect of exogenous adenosine on neurons has been confirmed, but its mechanism remains elusive. In this study, astrocytes were pretreated with adenosine, and the effects of an A2a receptor (A2aR) inhibitor (SCH58261) and A2b receptor (A2bR) inhibitor (PSB1115) on excitatory glutamate were investigated. An oxygen glucose deprivation/reoxygenation (OGD/R) and glutamate model was generated in vitro. Post-model assessment included expression levels of glutamate transporters (glt-1), gap junction protein (Cx43) and glutamate receptor (AMPAR), Na+-K+-ATPase activity, and diffusion distance of dyes. Glutamate and glutamine contents were determined at different time points. The results showed that (1) adenosine could improve the function of Na+-K+-ATPase, upregulate the expression of glt-1, and enhance the synthesis of glutamine in astrocytes. This effect was associated with A2aR activation but not with A2bR activation. (2) Adenosine could inhibit the expression of gap junction protein (Cx43) and reduce glutamate diffusion. Inhibition of A2aR attenuated adenosine inhibition of gap junction intercellular communication (GJIC) in the OGD/R model, while it enhanced adenosine inhibition of GJIC in the glutamate model, depending on the glutamate concentration. (3) Adenosine could cause AMPAR gradually entered the nucleus from the cytoplasm, thereby reducing the expression of AMPAR on the cell membrane. Taken together, the results indicate that adenosine plays a role of anti-excitatory toxicity effect in protection against neuronal death and the functional recovery of ischemic stroke mainly by targeting astrocytes, which are closely related to A2aR. The present study provided a scientific basis for adenosine prevention and ischemic stroke treatment, thereby providing a new approach for alleviating ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Al Rahim M, Hossain MA (2013) Genetic deletion of NP1 prevents hypoxic-ischemic neuronal death via reducing AMPA receptor synaptic localization in hippocampal neurons. J Am Heart Assoc 2(1):e006098. https://doi.org/10.1161/JAHA.112.006098

    Article  CAS  PubMed  Google Scholar 

  • Anderson MA, Ao Y, Sofroniew MV (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565:23–29

    CAS  PubMed  Google Scholar 

  • Arrubla J, Farrher E, Strippelmann J, Tse DHY, Grinberg F, Shah NJ et al (2017) Microstructural and functional correlates of glutamate concentration in the posterior cingulate cortex. J Neurosci Res 95(9):1796–1808

    CAS  PubMed  Google Scholar 

  • Atef RM, Agha AM, Abdel-Rhaman AA, Nassar NN (2018) The Ying and Yang of adenosine A1 and A2A receptors on ERK1/2 activation in a rat model of global cerebral ischemia reperfusion injury. Mol Neurobiol 55(2):1284–1298

    CAS  PubMed  Google Scholar 

  • Awasthi A, Ramachandran B, Ahmed S, Benito E, Shinoda Y, Nitzan N et al (2019) Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science 363(6422):eaav1483

    CAS  PubMed  Google Scholar 

  • Bai W, Li P, Ning YL, Peng Y, Xiong RP, Yang N et al (2018) Adenosine A2A receptor inhibition restores the normal transport of endothelial glutamate transporters in the brain. Biochem Biophys Res Commun 498(4):795–802

    CAS  PubMed  Google Scholar 

  • Bao L, Li RH, Li M, Jin MF, Li G, Han X et al (2017) Autophagy-regulated AMPAR subunit upregulation in in vitro oxygen glucose deprivation/reoxygenation-induced hippocampal injury. Brain Res 1668:65–71

    CAS  PubMed  Google Scholar 

  • Belousov AB, Fontes JD (2014) Neuronal gap junction coupling as the primary determinant of the extent of glutamate-mediated excitotoxicity. J Neural Transm (Vienna) 121(8):837–846. https://doi.org/10.1007/s00702-013-1109-7

    Article  CAS  Google Scholar 

  • Bissen D, Foss F, Acker-Palmer A (2019) AMPA receptors and their minions: auxiliary proteins in AMPA receptor trafficking. Cell Mol Life Sci (CMLS) 76(11):2133–2169

    CAS  Google Scholar 

  • Bobermin LD, Arus BA, Leite MC, Souza DO, Goncalves CA, Quincozes-Santos A (2016) Gap junction intercellular communication mediates ammonia-induced neurotoxicity. Neurotox Res 29(2):314–324

    CAS  PubMed  Google Scholar 

  • Brosnan JT, Brosnan ME (2013) Glutamate: a truly functional amino acid. Amino Acids 45(3):413–418

    CAS  PubMed  Google Scholar 

  • Castillo CA, Leon DA, Ballesteros-Yanez I, Albasanz JL, Martin M (2010) Glutamate differently modulates excitatory and inhibitory adenosine receptors in neuronal and glial cells. Neurochem Int 57(1):33–42

    CAS  PubMed  Google Scholar 

  • Ceprian M, Fulton D (2019) Glial cell AMPA receptors in nervous system health, injury and disease. Int J Mol Sci 20(10):E2450. https://doi.org/10.3390/ijms20102450

    Article  CAS  PubMed  Google Scholar 

  • Chang Y, Du C, Han L, Lv S, Zhang J, Bian G et al (2019) Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway. Neurochem Int 122:85–93

    CAS  PubMed  Google Scholar 

  • Chen G, Chen J, Ji X, Xi G, Zhang J (2015) Editorial for the third Pangu stroke conference. Exp Neurol 272:1–3

    PubMed  Google Scholar 

  • Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A et al (2016a) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533(7604):493–498

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YL, Zhang YN, Wang ZZ, Xu WG, Li RP, Zhang JD (2016b) Effects of adenosine metabolism in astrocytes on central nervous system oxygen toxicity. Brain Res 1635:180–189

    CAS  PubMed  Google Scholar 

  • Chen Q, Boire A, Jin X, Valiente M, Emrah EE, Lopez-Soto A et al (2017) Corrigendum: carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 544(7648):124

    CAS  PubMed  Google Scholar 

  • Chen W, Guo Y, Yang W, Chen L, Ren D, Wu C et al (2018) Phosphorylation of connexin 43 induced by traumatic brain injury promotes exosome release. J Neurophysiol 119(1):305–311

    CAS  PubMed  Google Scholar 

  • Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C et al (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504(7480):394–400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Covenas R, Mangas A, Sanchez ML, Cadena D, Husson M, Geffard M (2017) Generation of specific antisera directed against D-amino acids: focus on the neuroanatomical distribution of D-glutamate and other D-amino acids. Fol Histochem Cytobiol 55(4):177–189

    CAS  Google Scholar 

  • Dai SS, Zhou YG, Li W, An JH, Li P, Yang N et al (2010) Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci 30(16):5802–5810

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dal-Cim T, Poluceno GG, Lanznaster D, de Oliveira KA, Nedel CB, Tasca CI et al (2019) Guanosine prevents oxidative damage and glutamate uptake impairment induced by oxygen/glucose deprivation in cortical astrocyte cultures: involvement of A1 and A2A adenosine receptors and PI3K, MEK, and PKC pathways. Purinergic Signal 5(4):465–476. https://doi.org/10.1007/s11302-019-09679-w

    Article  CAS  Google Scholar 

  • Divito CB, Underhill SM (2014) Excitatory amino acid transporters: roles in glutamatergic neurotransmission. Neurochem Int 73:172–180

    CAS  PubMed  Google Scholar 

  • Eelen G, Dubois C, Cantelmo AR, Goveia J, Bruning U, DeRan M et al (2018) Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature 561(7721):63–69

    CAS  PubMed  Google Scholar 

  • Epifantseva I, Shaw RM (2018) Intracellular trafficking pathways of Cx43 gap junction channels. Biochim Biophys Biomembr 1860(1):40–47

    CAS  Google Scholar 

  • Farhy-Tselnicker I, Allen NJ (2018) Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. Neural Dev 13(1):7

    PubMed  PubMed Central  Google Scholar 

  • Fattorini G, Ripoli C, Cocco S, Spinelli M, Mattera A, Grassi C et al (2019) Glutamate/GABA co-release selectively influences postsynaptic glutamate receptors in mouse cortical neurons. Neuropharmacology 161:107737

    CAS  PubMed  Google Scholar 

  • Frankish H (2019) News from the international stroke conference, 2019. Lancet Neurol 18(4):337

    PubMed  Google Scholar 

  • Freitas-Andrade M, Naus CC (2016) Astrocytes in neuroprotection and neurodegeneration: the role of connexin43 and pannexin1. Neuroscience 323:207–221

    CAS  PubMed  Google Scholar 

  • Freitas-Andrade M, She J, Bechberger J, Naus CC, Sin WC (2018) Acute connexin43 temporal and spatial expression in response to ischemic stroke. J Cell Commun Signal 12(1):193–204

    PubMed  Google Scholar 

  • Fusco I, Cherchi F, Catarzi D, Colotta V, Varano F, Pedata F et al (2019) Functional characterization of a novel adenosine A2B receptor agonist on short-term plasticity and synaptic inhibition during oxygen and glucose deprivation in the rat CA1 hippocampus. Brain Res Bull 151:174–180. https://doi.org/10.1016/j.brainresbull.2019.05.018

    Article  CAS  PubMed  Google Scholar 

  • Genda EN, Jackson JG, Sheldon AL, Locke SF, Greco TM, O’Donnell JC et al (2011) Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 31(50):18275–18288

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goncalves FQ, Pires J, Pliassova A, Beleza R, Lemos C, Marques JM et al (2015) Adenosine A2b receptors control A1 receptor-mediated inhibition of synaptic transmission in the mouse hippocampus. Eur J Neurosci 41(7):878–888

    PubMed  Google Scholar 

  • Greer K, Chen J, Brickler T, Gourdie R, Theus MH (2017) Modulation of gap junction-associated Cx43 in neural stem/progenitor cells following traumatic brain injury. Brain Res Bull 134:38–46

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grenz A, Homann D, Eltzschig HK (2011) Extracellular adenosine: a safety signal that dampens hypoxia-induced inflammation during ischemia. Antioxid Redox Signal 15(8):2221–2234

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guillamon-Vivancos T, Gomez-Pinedo U, Matias-Guiu J (2015) Astrocytes in neurodegenerative diseases (I): function and molecular description. Neurología 30(2):119–129

    CAS  PubMed  Google Scholar 

  • Han BR, Lin SC, Espinosa K, Thorne PR, Vlajkovic SM (2019) Inhibition of the adenosine A2A receptor mitigates excitotoxic injury in organotypic tissue cultures of the rat cochlea. Cells 8(8):E877. https://doi.org/10.3390/cells8080877

    Article  CAS  PubMed  Google Scholar 

  • Hankey GJ (2014) Secondary stroke prevention. Lancet Neurol 13(2):178–194

    PubMed  Google Scholar 

  • Hansen JC, Bjorn-Yoshimoto WE, Bisballe N, Nielsen B, Jensen AA, Bunch L (2016) Beta-sulfonamido functionalized aspartate analogues as excitatory amino acid transporter inhibitors: distinct subtype selectivity profiles arising from subtle structural differences. J Med Chem 59(19):8771–8786

    CAS  PubMed  Google Scholar 

  • Haucke V (2000) Dissecting the ins and outs of excitement: glutamate receptors on the move. Nat Neurosci 3(12):1230–1232

    CAS  PubMed  Google Scholar 

  • Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C et al (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535(7613):551–555

    CAS  PubMed  PubMed Central  Google Scholar 

  • Herguedas B, Watson JF, Ho H, Cais O, Garcia-Nafria J, Greger IH (2019) Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP gamma8. Science 364(6438):eaav9011. https://doi.org/10.1126/science.aav9011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong S, Li T, Luo Y, Li W, Tang X, Ye Y et al (2018) Dynamic changes of astrocytes and adenosine signaling in rat hippocampus in post-status epilepticus model of epileptogenesis. Cell Mol Neurobiol 38(6):1227–1234

    CAS  PubMed  Google Scholar 

  • Hossmann KA (2003) Glutamate hypothesis of stroke. Fortsch Neurol Psychiatr 71(Suppl 1):S10–S15

    Google Scholar 

  • Jackson EK, Kotermanski SE, Menshikova EV, Dubey RK, Jackson TC, Kochanek PM (2017) Adenosine production by brain cells. J Neurochem 141(5):676–693

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K et al (2011) D-serine regulates cerebellar LTD and motor coordination through the delta2 glutamate receptor. Nat Neurosci 14(5):603–611

    CAS  PubMed  Google Scholar 

  • Kassubek R, Gorges M, Schocke M, Hagenston VAM, Huss A, Ludolph AC et al (2017) GFAP in early multiple sclerosis: a biomarker for inflammation. Neurosci Lett 657:166–170

    CAS  PubMed  Google Scholar 

  • Khatri R, McKinney AM, Swenson B, Janardhan V (2012) Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology 79(13 Suppl 1):S52–S57

    PubMed  Google Scholar 

  • Kitagawa H, Mori A, Shimada J, Mitsumoto Y, Kikuchi T (2002) Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats. Neurol Res 24(3):317–323

    CAS  PubMed  Google Scholar 

  • Kleopa KA, Sargiannidou I (2015) Connexins, gap junctions and peripheral neuropathy. Neurosci Lett 596:27–32

    CAS  PubMed  Google Scholar 

  • Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394(Pt 3):527–543

    CAS  PubMed  PubMed Central  Google Scholar 

  • Landhuis E (2018) Tapping into the brain’s star power. Nature 563(7729):141–143

    CAS  PubMed  Google Scholar 

  • Lee Y, Messing A, Su M, Brenner M (2008) GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56(5):481–493

    PubMed  Google Scholar 

  • Levy EI, Mokin M (2017) Stroke: Stroke thrombolysis and thrombectomy—not stronger together. Nat Rev Neurol 13(4):198–200

    PubMed  Google Scholar 

  • Li Q, Li QQ, Jia JN, Liu ZQ, Zhou HH, Mao XY (2019) Targeting gap junction in epilepsy: perspectives and challenges. Biomed Pharmacother 109:57–65. https://doi.org/10.1016/j.biopha.2018.10.068

    Article  CAS  PubMed  Google Scholar 

  • Lin X, Xu Q, Veenstra RD (2014) Functional formation of heterotypic gap junction channels by connexins-40 and -43. Channels 8(5):433–443

    PubMed  PubMed Central  Google Scholar 

  • Lin Z, Huang P, Huang S, Guo L, Xu X, Shen X et al (2018) Effect of adenosine and adenosine receptor antagonists on retinal Muller cell inwardly rectifying potassium channels under exogenous glutamate stimulation. Biomed Res Int 2018:2749257

    PubMed  PubMed Central  Google Scholar 

  • Liu YJ, Chen J, Li X, Zhou X, Hu YM, Chu SF et al (2019) Research progress on adenosine in central nervous system diseases. CNS Neurosci Ther 25(9):899–910. https://doi.org/10.1111/cns.13190

    Article  PubMed  PubMed Central  Google Scholar 

  • Madji HB, Blasco H, Coque E, Vourc'h P, Emond P, Corcia P et al (2018) The metabolic disturbances of motoneurons exposed to glutamate. Mol Neurobiol 55(10):7669–7676

    Google Scholar 

  • Matos M, Augusto E, Oliveira CR, Agostinho P (2008) Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades. Neuroscience 156(4):898–910

    CAS  PubMed  Google Scholar 

  • Matos M, Augusto E, Machado NJ, dos Santos-Rodrigues A, Cunha RA, Agostinho P (2012) Astrocytic adenosine A2A receptors control the amyloid-beta peptide-induced decrease of glutamate uptake. J Alzheimers Dis (JAD) 31(3):555–567

    CAS  Google Scholar 

  • Matos M, Augusto E, Agostinho P, Cunha RA, Chen JF (2013) Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-alpha2 controlling glutamate uptake in astrocytes. J Neurosci 33(47):18492–18502

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuoka I, Ohkubo S (2004) ATP- and adenosine-mediated signaling in the central nervous system: adenosine receptor activation by ATP through rapid and localized generation of adenosine by ecto-nucleotidases. J Pharmacol Sci 94(2):95–99

    CAS  PubMed  Google Scholar 

  • Mayorquin LC, Rodriguez AV, Sutachan JJ, Albarracin SL (2018) Connexin-mediated functional and metabolic coupling between astrocytes and neurons. Front Mol Neurosci 11:118

    PubMed  PubMed Central  Google Scholar 

  • Mazuel L, Schulte RF, Cladiere A, Speziale C, Lagree M, Leremboure M et al (2017) Intracerebral synthesis of glutamine from hyperpolarized glutamate. Magn Reson Med 78(4):1296–1305. https://doi.org/10.1002/mrm.26522

    Article  CAS  PubMed  Google Scholar 

  • Melani A, Dettori I, Corti F, Cellai L, Pedata F (2015) Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia. Neurol Sci 36(8):1441–1448. https://doi.org/10.1007/s10072-015-2160-y

    Article  PubMed  Google Scholar 

  • Meretoja A, Acciarresi M, Akinyemi RO, Campbell B, Dowlatshahi D, English C et al (2017) Stroke doctors: who are we? A World Stroke Organization survey. Int J Stroke 12(8):858–868

    PubMed  PubMed Central  Google Scholar 

  • Moidunny S, Vinet J, Wesseling E, Bijzet J, Shieh CH, van Ijzendoorn SC et al (2012) Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity. J Neuroinflammation 9:198

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oguro K, Jover T, Tanaka H, Lin Y, Kojima T, Oguro N et al (2001) Global ischemia-induced increases in the gap junctional proteins connexin 32 (Cx32) and Cx36 in hippocampus and enhanced vulnerability of Cx32 knock-out mice. J Neurosci 21(19):7534–7542

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okada M, Fukuyama K, Shiroyama T, Ueda Y (2019) Carbamazepine attenuates astroglial L-glutamate release induced by pro-inflammatory cytokines via chronically activation of adenosine A2A receptor. Int J Mol Sci 20(15):E3727. https://doi.org/10.3390/ijms20153727

    Article  CAS  PubMed  Google Scholar 

  • Pintor A, Galluzzo M, Grieco R, Pezzola A, Reggio R, Popoli P (2004) Adenosine A 2A receptor antagonists prevent the increase in striatal glutamate levels induced by glutamate uptake inhibitors. J Neurochem 89(1):152–156

    CAS  PubMed  Google Scholar 

  • Radojkovic M, Stojanovic M, Stanojevic G, Radojkovic D, Gligorijevic J, Ilic I et al (2017) Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury. Braz J Med Biol Res 50(8):e6185. https://doi.org/10.1590/1414-431X20176185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reiner A, Levitz J (2018) Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98(6):1080–1098

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ribeiro FM, Vieira LB, Pires RG, Olmo RP, Ferguson SS (2017) Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res 115:179–191. https://doi.org/10.1016/j.phrs.2016.11.013

    Article  CAS  PubMed  Google Scholar 

  • Rimmele TS, de Castro Abrantes H, Wellbourne-Wood J, Lengacher S, Chatton JY (2018) Extracellular potassium and glutamate interact to modulate mitochondria in astrocytes. ACS Chem Neurosci 9(8):2009–2015

    CAS  PubMed  Google Scholar 

  • Rimmele TS, Rosenberg PA (2016) GLT-1: The elusive presynaptic glutamate transporter. Neurochem Int 98:19–28

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson MB, Lee ML, DaSilva S (2020) Glutamate transporters and mitochondria: signaling, co-compartmentalization, functional coupling, and future directions. Neurochem Res 45(3):526–540. https://doi.org/10.1007/s11064-020-02974-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rose CR, Ziemens D, Untiet V, Fahlke C (2018) Molecular and cellular physiology of sodium-dependent glutamate transporters. Brain Res Bull 136:3–16

    CAS  PubMed  Google Scholar 

  • Schousboe A, Waagepetersen HS (2005) Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res 8(3–4):221–225

    CAS  PubMed  Google Scholar 

  • Sekiguchi KJ, Shekhtmeyster P, Merten K, Arena A, Cook D, Hoffman E et al (2016) Imaging large-scale cellular activity in spinal cord of freely behaving mice. Nat Commun 7:11450

    PubMed  PubMed Central  Google Scholar 

  • Seydyousefi M, Moghanlou AE, Metz GAS, Gursoy R, Faghfoori MH, Mirghani SJ, Faghfoori Z (2019) Exogenous adenosine facilitates neuroprotection and functional recovery following cerebral ischemia in rats. Brain Res Bull 153:250–256

    CAS  PubMed  Google Scholar 

  • Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ et al (2013) Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alpha B-crystallin. Nature 494(7435):90–94

    CAS  PubMed  Google Scholar 

  • Sheikhbahaei S, Turovsky EA, Hosford PS, Hadjihambi A, Theparambil SM, Liu B et al (2018) Astrocytes modulate brainstem respiratory rhythm-generating circuits and determine exercise capacity. Nat Commun 9(1):370

    PubMed  PubMed Central  Google Scholar 

  • Sheng M, Nakagawa T (2002) Neurobiology: glutamate receptors on the move. Nature 417(6889):601–602

    CAS  PubMed  Google Scholar 

  • Singh L, Kulshrestha R, Singh N, Jaggi AS (2018a) Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection. Korean J Physiol Pharmacol 22(3):225–234

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singh L, Virdi JK, Maslov LN, Singh N, Jaggi AS (2018b) Investigating the possible mechanisms involved in adenosine preconditioning-induced cardioprotection in rats. Cardiovasc Ther 36(3):e12328

    PubMed  Google Scholar 

  • Singh H, Kumar M, Singh N, Jaggi AS (2019) Late phases of cardioprotection during remote ischemic preconditioning and adenosine preconditioning involve activation of neurogenic pathway. J Cardiovasc Pharmacol 73(2):63–69

    CAS  PubMed  Google Scholar 

  • Smail H, Baste JM, Gay A, Begueret H, Noel R, Morin JP et al (2016) Role of inflammatory cells and adenosine in lung ischemia reoxygenation injury using a model of lung donation after cardiac death. Exp Lung Res 42(3):131–141

    CAS  PubMed  Google Scholar 

  • Smith M, Reddy U, Robba C (2019) Acute ischaemic stroke: challenges for the intensivist. Intensive Care Med 45(9):1177–1189. https://doi.org/10.1007/s00134-019-05705-y

    Article  CAS  PubMed  Google Scholar 

  • Solan JL, Lampe PD (2014) Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett 588(8):1423–1429

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun K, Fan J, Han J (2015) Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage. Acta Pharm Sin B 5(1):8–24

    PubMed  PubMed Central  Google Scholar 

  • Thevenin AF, Margraf RA, Fisher CG, Kells-Andrews RM, Falk MM (2017) Phosphorylation regulates connexin43/ZO-1 binding and release, an important step in gap junction turnover. Mol Biol Cell 28(25):3595–3608

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tovar KR, Westbrook GL (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34(2):255–264

    CAS  PubMed  Google Scholar 

  • Trabelsi Y, Amri M, Becq H, Molinari F, Aniksztejn L (2017) The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors. Glia 65(2):401–415

    PubMed  Google Scholar 

  • Vicario N, Calabrese G, Zappala A, Parenti C, Forte S, Graziano ACE et al (2017) Inhibition of Cx43 mediates protective effects on hypoxic/reoxygenated human neuroblastoma cells. J Cell Mol Med 21(10):2563–2572

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu LY, Yu XL, Feng LY (2015) Connexin 43 stabilizes astrocytes in a stroke-like milieu to facilitate neuronal recovery. Acta Pharmacol Sin 36(8):928–938

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yaghi S, Willey JZ, Cucchiara B, Goldstein JN, Gonzales NR, Khatri P et al (2017) Treatment and outcome of hemorrhagic transformation after intravenous alteplase in acute ischemic stroke: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 48(12):e343–e361. https://doi.org/10.1161/STR.0000000000000152

    Article  PubMed  Google Scholar 

  • Yuan Q, Jia HX, Li SQ, Xiao-Zhang, Wu YJ, Feng L et al (2019) The role of adenosine in up-regulation of p38 MAPK and ERK during limb ischemic preconditioning-induced brain ischemic tolerance. Brain Res 1707:172–183

  • Zachariassen LG, Katchan L, Jensen AG, Pickering DS, Plested AJ, Kristensen AS et al (2016) Structural rearrangement of the intracellular domains during AMPA receptor activation. Proc Natl Acad Sci USA 113(27):E3950–E3959

    CAS  PubMed  Google Scholar 

  • Zhou M, Wang H, Zhu J, Chen W, Wang L, Liu S et al (2016) Cause-specific mortality for 240 causes in China during 1990–2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. Lancet 387(10015):251–272

    PubMed  Google Scholar 

  • Zhou Y, Zeng X, Li G, Yang Q, Xu J, Zhang M et al (2019) Inactivation of endothelial adenosine A2A receptors protects mice from cerebral ischaemia-induced brain injury. Brit J Pharmacol 176(13):2250–2263

    CAS  Google Scholar 

Download references

Funding

This work was supported by the Hunan University of Chinese Medicine First-class Disciple Construction Project (201803), Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces (2016TP2008), Hunan Provincial Natural Science Fund (S2019JJQNJJ1064), Project of NDRC and State Administration of Traditional Chinese Medicine (ZYBZH-Y-HUN-24).

Author information

Authors and Affiliations

  1. College of Pharmacy, Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, China

    Yingjiao Liu, Yaomei Hu, Songwei Yang, Xun Li, Qidi Ai, Siyu Ren, Huiqin Wang, Limin Gong & Nai-Hong Chen

  2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Yingjiao Liu, Shifeng Chu, Xun Li & Nai-Hong Chen

  3. Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, 510631, China

    Qinglian Zheng, Xin Xu & Nai-Hong Chen

Authors
  1. Yingjiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shifeng Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaomei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Songwei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qinglian Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qidi Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Siyu Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huiqin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Limin Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nai-Hong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NC and YL involved in conceptualization and methodology; YL, YH, and SC participated in validation and writing the original draft; YL, XL, QZ, and QA did formal analysis; YL, SY, SR, HW, XX, and LG involved in writing, review, and editing of the manuscript. All authors approved the final submission.

Corresponding author

Correspondence to Nai-Hong Chen.

Ethics declarations

Conflict of interest

All the authors declare no conflicts of interest.

Informed Consent

All participants in this study were informed and gave an informed written consent.

Research Involving Animals

All procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Peking Union Medical College and Chinese Academy of Medical Sciences.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Chu, S., Hu, Y. et al. Exogenous Adenosine Antagonizes Excitatory Amino Acid Toxicity in Primary Astrocytes. Cell Mol Neurobiol 41, 687–704 (2021). https://doi.org/10.1007/s10571-020-00876-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-020-00876-5

Keywords

Search

Navigation