Skip to main content
SpringerLink
Log in

Adenosine Receptors and Neuroinflammation

  • Chapter
  • First Online:
The Adenosine Receptors

Part of the book series: The Receptors ((REC,volume 34))

Abstract

Neuroinflammation, mainly sustained by microglial activation, is one of the hallmarks of many neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. A broad spectrum of functionally distinct microglial phenotypes has been described, differently affecting the central nervous system (CNS) homeostasis. Manipulating the activation state of microglia toward neuroprotective functions can thus be of therapeutic benefit in a number of CNS diseases.

Adenosine is an endogenous neuromodulator acting through the stimulation of four receptor subtypes, namely, A1, A2A, A2B, and A3 receptors (Rs). Among its numerous effects, adenosine plays an important immunoregulatory role in the CNS. A2AR activation, in particular, appears to play a crucial role mainly by regulating microglial function. Emerging evidence indicates that such receptors may mediate different and even opposite effects on brain inflammation according to the stage of the pathological condition and to the different inflammatory cell types involved in that particular stage. The complex role of A2ARs in controlling neuroinflammation is strongly dependent also on the interplay with other neurotransmitters.

In this chapter, we will critically discuss the role of adenosine receptors in neuroinflammation (with particular emphasis on the A2AR subtype), and its possible relevance to neurodegeneration.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ajmone-Cat MA, Mancini M, De Simone R et al (2013) Microglial polarization and plasticity: evidence from organotypic hippocampal slice cultures. Glia 61(10):1698–1711

    Article  PubMed  Google Scholar 

  • Ajmone-Cat MA, D'Urso MC, di Blasio G et al (2016) Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells. Brain Behav Immun 55:225–235

    Article  PubMed  CAS  Google Scholar 

  • Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21(3):383–421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Amor S, Woodroofe MN (2014) Innate and adaptive immune responses in neurodegeneration and repair. Immunology 141(3):287–291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ascherio A, Zhang SM, Hernán MA et al (2001) Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 50:56–63

    Article  PubMed  CAS  Google Scholar 

  • Bartlett DM, Cruickshank TM, Hannan AJ et al (2016) Neuroendocrine and neurotrophic signaling in Huntington's disease: implications for pathogenic mechanisms and treatment strategies. Neurosci Biobehav Rev 71:444–454

    Article  PubMed  CAS  Google Scholar 

  • Beamer E, Gölöncsér F, Horváth G et al (2016) Purinergic mechanisms in neuroinflammation: an update from molecules to behavior. Neuropharmacology 104:94–104

    Article  PubMed  CAS  Google Scholar 

  • Bellaver B, Dos Santos JP, Leffa DT et al (2018) Systemic inflammation as a driver of brain injury: the astrocyte as an emerging player. Mol Neurobiol 55:2685–2695

    Google Scholar 

  • Bender AS, Hertz L (1986) Similarities of adenosine uptake systems in astrocytes and neurons in primary cultures. Neurochem Res 11:1507–1524

    Article  PubMed  CAS  Google Scholar 

  • Björkqvist M, Wild EJ, Thiele J et al (2008) A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J Exp Med 205(8):1869–1877

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blackburn MR, Vance CO, Morschl E et al (2009) Adenosine receptors and inflammation. Handb Exp Pharmacol 193:215–269

    Article  CAS  Google Scholar 

  • Blum D, Galas MC, Pintor A et al (2003) A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists. J Neurosci 23:5361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boillée S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52(1):39–59

    Article  PubMed  CAS  Google Scholar 

  • Boison D (2012) Adenosine dysfunction in epilepsy. Glia 60:1234–1243

    Article  PubMed  Google Scholar 

  • Bradford J, Shin JY, Roberts M et al (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A 106(52):22480–22485

    Article  PubMed  PubMed Central  Google Scholar 

  • Bradford J, Shin JY, Roberts M et al (2010) Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285(14):10653–10661

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brambilla R, Cottini L, Fumagalli M et al (2003) Blockade of A2A adenosine receptors prevents basic fibroblast growth factor- induced reactive astrogliosis in rat striatal primary astrocytes. Glia 43:190–194

    Article  PubMed  Google Scholar 

  • Brochard V, Combadière B, Prigent A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1):182–192

    PubMed  CAS  Google Scholar 

  • Brodie C, Blumberg PM, Jackobson KA (1998) Activation of the A2A adenosine receptor inhibits nitric oxide production in glial cells. FEBS Lett 429:139–142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Calabrese V, Santoro A, Monti D et al (2017) Aging and Parkinson's disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic Biol Med 115:80–91

    Article  PubMed  CAS  Google Scholar 

  • Carnevale D, Mascio G, Ajmone-Cat MA et al (2012) Role of neuroinflammation in hypertension-induced brain amyloid pathology. Neurobiol Aging 33(1):e19–e29

    Article  CAS  Google Scholar 

  • Carroll JB, Bates GP, Steffan J et al (2015) Treating the whole body in Huntington's disease. Lancet Neurol 14(11):1135–1142

    Article  PubMed  Google Scholar 

  • Chandra G, Rangasamy SB, Roy A et al (2016) Neutralization of RANTES and Eotaxin prevents the loss of dopaminergic neurons in a mouse model of Parkinson disease. J Biol Chem 291(29):15267–15281

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14(15):1490–1499

    Article  PubMed  CAS  Google Scholar 

  • Choi IY, Lee JC, Ju C et al (2011) A3 adenosine receptor agonist reduces brain ischemic injury and inhibits inflammatory cell migration in rats. Am J Pathol 179(4):2042–2052

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ciccarelli R, Di Iorio P, Bruno V et al (1999) Activation of A(1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocytes. Glia 27(3):275–281

    Article  PubMed  CAS  Google Scholar 

  • Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2(11):806–819

    Article  PubMed  CAS  Google Scholar 

  • Condello C, Yuan P, Schain A et al (2015) Microglia constitute a barrier that prevents neurotoxic protofibrillar Ab42 hotspots around plaques. Nat Commun 6:61–76

    Article  CAS  Google Scholar 

  • Crotti A, Glass CK (2015) The choreography of neuroinflammation in Huntington's disease. Trends Immunol 36(6):364–373

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Csóka B, Németh ZH, Rosenberger P et al (2010) A2B adenosine receptors protect against sepsis-induced mortality by dampening excessive inflammation. J Immunol 185(1):542–550

    Article  PubMed  CAS  Google Scholar 

  • Cunha RA (2016) How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 139(6):1019–1055

    Article  PubMed  CAS  Google Scholar 

  • Cunha RA, Agostinho PM (2010) Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. J Alzheimers Dis 20(Suppl 1):95–116

    Article  CAS  Google Scholar 

  • da Rocha Lapa F, Macedo Júnior SJ, Cerutti ML et al (2014) Pharmacology of adenosine receptors and their Signaling role in immunity and inflammation. In: Gowder S (ed) Pharmacology and therapeutics. InTech, Rijeka

    Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dall'Igna OP, Porciuncula LO, Souza DO et al (2003) Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br J Pharmacol 138:1207–1209

    Article  PubMed  CAS  Google Scholar 

  • Dall'Igna OP, Fett P, Gomes MW et al (2007) Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25–35)-induced cognitive deficits in mice. Exp Neurol 203:241–245

    Article  PubMed  CAS  Google Scholar 

  • De Simone R, Ajmone-Cat MA, Minghetti L (2004) Atypical antiinflammatory activation of microglia induced by apoptotic neurons: possible role of phosphatidylserine-phosphatidylserine receptor interaction. Mol Neurobiol 29(2):197–212

    Article  PubMed  Google Scholar 

  • De Simone R, Niturad CE, De Nuccio C et al (2010) TGF-β and LPS modulate ADP-induced migration of microglial cells through P2Y1 and P2Y12 receptor expression. J Neurochem 115(2):450–459

    Article  PubMed  CAS  Google Scholar 

  • Depboylu C, Schäfer MK, Arias-Carrión O et al (2011) Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease. J Neuropathol Exp Neurol 70(2):125–132

    Article  PubMed  CAS  Google Scholar 

  • Dobson L, Träger U, Farmer R et al (2016) Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells. J Neurochem 137(5):782–794

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eikelenboom P, Veerhuis R, Scheper W et al (2006) The significance of neuroinflammation in understanding Alzheimer's disease. J Neural Transm 113(11):1685–1695

    Article  PubMed  CAS  Google Scholar 

  • Engelhardt JI, Tajti J, Appel SH (1993) Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch Neurol 50(1):30–36

    Article  PubMed  CAS  Google Scholar 

  • Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145

    Article  PubMed  CAS  Google Scholar 

  • Feoktistov I, Biaggioni I (2011) Role of adenosine A2B receptors in inflammation. Adv Pharmacol 61:115–144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Frakes AE, Ferraiuolo L, Haidet-Phillips AM et al (2014) Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron 81(5):1009–1023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Franciosi S, Ryu JK, Shim Y et al (2011) Age-dependent neurovascular abnormalities and altered microglial morphology in the YAC128 mouse model of Huntington disease. Neurobiol Dis 45:438–449

    Article  PubMed  CAS  Google Scholar 

  • Fredholm BB, IJzerman AP, Jacobson KA et al (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53(4):527–552

    PubMed  CAS  Google Scholar 

  • Geiger JD, Buscemi L, Fotheringham JA (2007) Role of adenosine in the control of inflammatory events associated with acute and chronic neurodegenerative disorders. In: Cronstein B, Szabo C, Hasko G (eds) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. CRC Press, Taylor and Francis, pp 213–235

    Google Scholar 

  • Genovese T, Melani A, Esposito E et al (2009) The selective adenosine A2A receptor agonist CGS21680 reduces JNK MAPK activation in oligodendrocytes ininjured spinal cord. Shock 32(Suppl6):S578–S585

    Article  CAS  Google Scholar 

  • Gessi S, Merighi S, Stefanelli A et al (2013) A(1) and A(3) adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes. Pharmacol Res 76:157–170

    Article  PubMed  CAS  Google Scholar 

  • Golder FJ, Ranganathan L, Satriotomo I et al (2008) Spinal adenosine A2A receptor activation elicits long-lasting phrenic motor facilitation. J Neurosci 28:2033–2042

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gomes CV, Kaster MP, Tomé AR et al (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808(5):1380–1399

    Article  PubMed  CAS  Google Scholar 

  • Gyoneva S, Shapiro L, Lazo C et al (2014) Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson's disease. Neurobiol Dis 67:191–202

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23(3):249–256

    Article  PubMed  CAS  Google Scholar 

  • Hamelin L, LagardeJ DG et al (2016) Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139:1252–1264

    Article  PubMed  Google Scholar 

  • Haselkorn ML, Shellington DK, Jackson EK et al (2010) Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice. J Neurotrauma 27(5):901–910

    Article  PubMed  PubMed Central  Google Scholar 

  • Haskó G, Pacher P, Vizi ES et al (2005) Adenosine receptor signaling in the brain immune system. Trends Pharmacol Sci 26(10):511–516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Henkel JS, Beers DR, Wen S et al (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 5(1):64–79

    Article  PubMed  CAS  Google Scholar 

  • Hickey WF, Hsu BL, Kimura H (1991) T-lymphocyte entry into the central nervous system. J Neurosci Res 28(2):254–260

    Article  PubMed  CAS  Google Scholar 

  • Hong S, Beja-Glasser VF, Nfonoyim BM et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hovden H, Frederiksen JL, Pedersen SW (2013) Immune system alterations in amyotrophic lateral sclerosis. Acta Neurol Scand 128(5):287–296

    PubMed  CAS  Google Scholar 

  • Jansen AH, van Hal M, Op den Kelder IC et al (2017) Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific. Glia 65(1):50–61

    Article  PubMed  Google Scholar 

  • Jiang P, Dickson DW (2018) Parkinson’s disease: experimental models and reality. Acta Neuropathol 135:13–32

    Google Scholar 

  • Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386(9996):896–912

    Article  PubMed  CAS  Google Scholar 

  • Khakh BS, Beaumont V, Cachope R et al (2017) Unravelling and exploiting astrocyte dysfunction in Huntington's disease. Trends Neurosci 40(7):422–437

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koscsó B, Csóka B, Selmeczy Z et al (2012) Adenosine augments IL-10 production by microglial cells through an A2B adenosine receptor-mediated process. J Immunol 188(1):445–453

    Article  PubMed  CAS  Google Scholar 

  • Lee HK, Choi SS, Han KJ et al (2004) Roles of adenosine receptors in the regulation of kainic acid-induced neurotoxic responses in mice. Brain Res Mol Brain Res 125:76–85

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Jhun BS, Oh YT et al (2006) Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI 3-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells. Neurosci Lett 396(1):1–6

    Article  PubMed  CAS  Google Scholar 

  • Liang D, Zuo A, Shao H et al (2014) Anti-inflammatory or proinflammatory effect of an adenosine receptor agonist on the Th17 auto-immune response is inflammatory environment-dependent. J Immunol 193:5498–5505

    Article  PubMed  CAS  Google Scholar 

  • Liddelow SA, Guttenplan KA, Clarke LE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Luongo L, Guida F, Imperatore R et al (2014) The A1 adenosine receptor as a new player in microglia physiology. Glia 62(1):122–132

    Article  PubMed  CAS  Google Scholar 

  • Lyons SA, Pastor A, Ohlemeyer C et al (2000) Distinct physiologic properties of microglia and blood-borne cells in rat brain slices after permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab 20:1537–1549

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2001) Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging 22(6):799–809

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2008) Glial reactions in Parkinson's disease. Mov Disord 23(4):474–483

    Article  PubMed  Google Scholar 

  • Melani A, Corti F, Stephan H et al (2012) Ecto-ATPase inhibition: ATP and adenosine release under physiological and ischemic in vivo conditions in the rat striatum. Exp Neurol 233:193–204

    Article  PubMed  CAS  Google Scholar 

  • Melani A, Corti F, Cellai L et al (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

    Article  PubMed  CAS  Google Scholar 

  • Merighi S, Borea PA, Stefanelli A et al (2015) A2A and A2B adenosine receptors affect HIF-1a signaling in activated primary microglial cells. Glia 63:1933–1952

    Article  PubMed  Google Scholar 

  • Merighi S, Bencivenni S, Vincenzi F et al (2017) A2B adenosine receptors stimulate IL-6 production in primary murine microglia through p38 MAPK kinase pathway. Pharmacol Res 117:9–19

    Article  PubMed  CAS  Google Scholar 

  • Mills JH, Thompson LF, Mueller C et al (2008) CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 105:9325–9330

    Article  PubMed  PubMed Central  Google Scholar 

  • Mills JH, Kim DG, Krenz A et al (2012) A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J Immunol 188:5713–5722

    Article  PubMed  CAS  Google Scholar 

  • Mina E, van Roon-Mom W, Hettne K et al (2016) Common disease signatures from gene expression analysis in Huntington's disease human blood and brain. Orphanet J Rare Dis 11(1):97

    Article  PubMed  PubMed Central  Google Scholar 

  • Minghetti L, Ajmone-Cat MA, De Berardinis MA et al (2005) Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Rev 48(2):251–256

    Article  PubMed  CAS  Google Scholar 

  • Minghetti L, Greco A, Potenza RL et al (2007) Effects of the adenosine A2A receptor antagonist SCH 58621 on cyclooxygenase-2 expression, glial activation, and brain-derived neurotrophic factor availability in a rat model of striatal neurodegeneration. J Neuropathol Exp Neurol 66(5):363–371

    Article  PubMed  CAS  Google Scholar 

  • Morelli M, Carta AR, Jenner P (2009) Adenosine A2A receptors and Parkinson's disease. Handb Exp Pharmacol 193:589–615

    Article  CAS  Google Scholar 

  • Morelli M, Carta AR, Kachroo A et al (2010) Pathophysiological roles for purines: adenosine, caffeine and urate. Prog Brain Res 183:183–208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26(3):349–354

    Article  PubMed  CAS  Google Scholar 

  • Murdock BJ, Bender DE, Segal BM et al (2015) The dual roles of immunity in ALS: injury overrides protection. Neurobiol Dis 77:1–12

    Article  PubMed  CAS  Google Scholar 

  • Nalls MA, Pankratz N, Lill CM et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ng SK, Higashimori H, Tolman M et al (2015) Suppression of Adenosine A2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis. Exp Neurol 267:115–122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Obeso JA, Stamelou M, Goetz CG et al (2017) Past, present, and future of Parkinson's disease: a special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord 32(9):1264–1310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ohsawa K, Sanagi T, Nakamura Y et al (2012) Adenosine A3 receptor is involved in ADP-induced microglial process extension and migration. J Neurochem 121:217–227

    Article  PubMed  CAS  Google Scholar 

  • Orr AG, Hsiao EC, Wang MM et al (2015) Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 18:423–434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Orr AG, Lo I, Schumacher H et al (2017) Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis 110:29–36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pedata F, Dettori I, Coppi E et al (2016) Purinergic signalling in brain ischemia. Neuropharmacology 104:105–130

    Article  PubMed  CAS  Google Scholar 

  • Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 7(2):161–167

    Article  PubMed  CAS  Google Scholar 

  • Pierri M, Vaudano E, Sager T et al (2005) KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse. Neuropharmacology 48(4):517–524

    Article  PubMed  CAS  Google Scholar 

  • Pinna A (2014) Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs 28:455–474

    Article  PubMed  CAS  Google Scholar 

  • Politis M, Lahiri N, Niccolini F et al (2015) Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers. Neurobiol Dis 83:115–121

    Article  PubMed  CAS  Google Scholar 

  • Popoli P, Pepponi R (2012) Potential therapeutic relevance of Adenosine A2B and A2A receptors in the central nervous system. CNS Neurol Disord Drug Targets 11:664–674

    Article  PubMed  CAS  Google Scholar 

  • Popoli P, Pintor A, Domenici MR et al (2002) 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. J Neurosci 22(5):1967–1975

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Popoli P, Blum D, Martire A et al (2007) Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease. Prog Neurobiol 81:331–348

    Article  PubMed  CAS  Google Scholar 

  • Potenza RL, Armida M, Ferrante A et al (2013) Effects of chronic caffeine intake in a mouse model of amyo-trophic lateral sclerosis. J Neurosci Res 91:585–592

    Article  PubMed  CAS  Google Scholar 

  • Potenza RL, De Simone R, Armida M et al (2016) Fingolimod: a disease-modifier drug in a mouse model of amyotrophic lateral sclerosis. Neurotherapeutics 13(4):918–927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Przedborski S (2007) Neuroinflammation and Parkinson's disease. Handb Clin Neurol 83:535–551

    Article  PubMed  Google Scholar 

  • Rahman A (2009) The role of adenosine in Alzheimer's disease. Curr Neuropharmacol 7(3):207–216

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ransohoff RM (2016) How neuroinflammation contributes to neurodegeneration. Science 353(6301):777–783

    Article  PubMed  CAS  Google Scholar 

  • Rathbone MP, Middlemiss PJ, DeLuca B et al (1991) Extracellular guanosine increases astrocyte cAMP: inhibition by adenosine A2 antagonists. Neuroreport 2:661–664

    Article  PubMed  CAS  Google Scholar 

  • Rebola N, Simões AP, Canas PM et al (2011) Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J Neurochem 117(1):100–111

    Article  PubMed  CAS  Google Scholar 

  • Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17(1):17–23

    Article  PubMed  CAS  Google Scholar 

  • Salter MW, Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23(9):1018–1027

    Article  PubMed  CAS  Google Scholar 

  • Sapp E, Kegel KB, Aronin N et al (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60(2):161–172

    Article  PubMed  CAS  Google Scholar 

  • Saura J, Angulo E, Ejarque A et al (2005) Adenosine A2A receptor stimulation potentiates nitric oxide release by activated microglia. J Neurochem 95(4):919–929

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M, Butovsky O, Bruck W et al (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29(2):68–74

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 8(6):595–608

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shin JY, Fang ZH, Yu ZX et al (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171(6):1001–1012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Si QS, Nakamura Y, Schubert P et al (1996) Adenosine and propentofylline inhibit the proliferation of cultured microglial cells. Exp Neurol 137:345–349

    Article  PubMed  CAS  Google Scholar 

  • Silvestroni A, Faull RL, Strand AD et al (2009) Distinct neuroinflammatory profile in post-mortem human Huntington's disease. Neuroreport 20(12):1098–1103

    Article  PubMed  Google Scholar 

  • Spangenberg EE, Green KN (2017) Inflammation in Alzheimer's disease: lessons learned from microglia-depletion models. Brain Behav Immun 61:1–11

    Article  PubMed  CAS  Google Scholar 

  • Stone TW, Behan WMH (2007) Interleukin-1𝛽 but not tumor necrosis factor-𝛼 potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist. J Neurosci Res 85:1077–1085

    Google Scholar 

  • Studer FE, Fedele DE, Marowsky A et al (2006) Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme. Neuroscience 142:125–137

    Article  PubMed  CAS  Google Scholar 

  • Sun Q, Xie N, Tang B et al (2017) Alzheimer's disease: from genetic variants to the distinct pathological mechanisms. Front Mol Neurosci 10:319

    Article  PubMed  PubMed Central  Google Scholar 

  • Synowitz M, Glass R, Farber K et al (2006) A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res 66:8550–8557

    Article  PubMed  CAS  Google Scholar 

  • Tai YF, Pavese N, Gerhard A et al (2007) Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 130:1759–1766

    Article  PubMed  Google Scholar 

  • Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37(3):510–518

    Article  PubMed  CAS  Google Scholar 

  • Thal DR (2012) The role of astrocytes in amyloid β-protein toxicity and clearance. Exp Neurol 236(1):1–5

    Article  PubMed  CAS  Google Scholar 

  • Troost D, van den Oord JJ, de Jong JM et al (1989) Lymphocytic infiltration in the spinal cord of patients with amyotrophic lateral sclerosis. Clin Neuropathol 8(6):289–294

    PubMed  CAS  Google Scholar 

  • Tsutsui S, Schnermann J, Noorbakhsh F et al (2004) A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 24:1521–1529

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Turner MR, Cagnin A, Turkheimer FE et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15(3):601–609

    Article  PubMed  CAS  Google Scholar 

  • van der Burg JM, Björkqvist M, Brundin P (2009) Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol 8(8):765–774

    Article  PubMed  Google Scholar 

  • van der Putten C, Zuiderwijk-Sick EA, van Straalen L et al (2009) Differential expression of adenosine A3 receptors controls adenosine A2A receptor-mediated inhibition of TLR responses in microglia. J Immunol 182(12):7603–7612

    Article  PubMed  CAS  Google Scholar 

  • Vazquez JF, Clement HW, Sommer O et al (2008) Local stimulation of the adenosine A2B receptors induces an increased release of IL-6 in mouse striatum: an in vivo microdialysis study. J Neurochem 105:904–909

    Article  PubMed  CAS  Google Scholar 

  • Vincenzi F, Corciulo C, Targa M et al (2013) A2A adenosine receptors are up-regulated in lym- phocytes from amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Front Degener 14:406–413

    Article  CAS  Google Scholar 

  • von Lubitz DK (1999) Adenosine and cerebral ischemia: therapeutic future or death of a brave concept? Eur J Pharmacol 371:85–102

    Article  Google Scholar 

  • von Lubitz DK, Simpson KL, Lin RC (2001) Right thing at a wrong time? Adenosine A3 receptors and cerebroprotection in stroke. Ann N Y Acad Sci 939:85–96

    Article  Google Scholar 

  • Wei CJ, Li W, Chen JF (2011) Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies. Biochim Biophys Acta 1808(5):1358–1379

    Article  PubMed  CAS  Google Scholar 

  • Wiese S, Jablonka S, Holtmann B et al (2007) Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB. Proc Natl Acad Sci U S A 104:17210–17215

    Article  PubMed  PubMed Central  Google Scholar 

  • Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12(9):1005–1015

    PubMed  CAS  Google Scholar 

  • Yanpallewar SU, Barrick CA, Buckley H et al (2012) Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis. PLoS One 7:e39946

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu L, Huang Z, Mariani J et al (2004) Selective inactivation or reconstitution of adenosine A2A receptors in bone marrow cells reveals their significant contribution to the development of ischemic brain injury. Nat Med 10:1081–1087

    Article  PubMed  CAS  Google Scholar 

  • Yu L, Shen HY, Coelho JE et al (2008) Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms. Ann Neurol 63(3):338–346

    Article  PubMed  CAS  Google Scholar 

  • Zeron MM, Hansson O, Chen N et al (2002) Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33(6):849–860

    Article  PubMed  CAS  Google Scholar 

  • Zhang R, Gascon R, Miller RG et al (2005) Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol 159(1–2):215–224

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Gao JH, Yan ZF et al (2018) Minimally toxic dose of lipopolysaccharide and α-synuclein oligomer elicit synergistic dopaminergic neurodegeneration: role and mechanism of microglial NOX2 activation. Mol Neurobiol 55 (1): 619–632.

    Google Scholar 

  • Zhao W, Beers DR, Appel SH (2013) Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol 8(4):888–899

    Article  PubMed  PubMed Central  Google Scholar 

  • Zimmermann H (2000) Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedeberg's Arch Pharmacol 362:299–309

    Article  CAS  Google Scholar 

  • Zucca FA, Segura-Aguilar J, Ferrari E et al (2017) Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease. Prog Neurobiol 155:96–119

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Pharmacological Research and Experimental Therapeutics, Istituto Superiore di Sanità, Rome, Italy

    Antonella Ferrante, Roberta De Simone & Maria Antonietta Ajmone-Cat

  2. Research Coordination and Support Service, Istituto Superiore di Sanità, Rome, Italy

    Luisa Minghetti

  3. National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy

    Patrizia Popoli

Authors
  1. Antonella Ferrante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta De Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Antonietta Ajmone-Cat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luisa Minghetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrizia Popoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrizia Popoli .

Editor information

Editors and Affiliations

  1. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Pier Andrea Borea

  2. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Katia Varani

  3. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Gessi

  4. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Stefania Merighi

  5. Department of Medical Sciences, University of Ferrara, Ferrara, Italy

    Fabrizio Vincenzi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ferrante, A., De Simone, R., Ajmone-Cat, M.A., Minghetti, L., Popoli, P. (2018). Adenosine Receptors and Neuroinflammation. In: Borea, P., Varani, K., Gessi, S., Merighi, S., Vincenzi, F. (eds) The Adenosine Receptors. The Receptors, vol 34. Humana Press, Cham. https://doi.org/10.1007/978-3-319-90808-3_9

Download citation

Publish with us

Policies and ethics

Search

Navigation