Molecular Neurobiology

, Volume 56, Issue 4, pp 2881–2895 | Cite as

Resveratrol Modulates and Reverses the Age-Related Effect on Adenosine-Mediated Signalling in SAMP8 Mice

  • A. Sánchez-Melgar
  • J. L. AlbasanzEmail author
  • V. Palomera-Ávalos
  • M. Pallàs
  • M. Martín


Resveratrol (RSV) is a natural compound present in berries, grapes and red wine that has shown some neuroprotective properties, but the mechanism by which RSV exhibits its protective role is not very well understood yet. Little is known about the effect of RSV on adenosinergic system, a system regulated in an age-dependent manner in SAMP8 mice, widely considered as an Alzheimer’s model. Therefore, the aim of the present work was to assess whether RSV intake was able to modulate the adenosine-mediated signalling in SAMP8 mice. Data showed herein clearly demonstrate the ability of RSV to modulate adenosine receptor gene expression as well as transduction pathway mediated by receptors expressed on plasma membrane. Interestingly, this polyphenol was able to reverse the age-related loss of adenosine A1 receptors and its corresponding signalling pathway. Moreover, adenosine A2A receptors were not modulated by aging or RSV, but A2A-mediated signalling was completely desensitized after RSV treatment compared to untreated mice. Enzymes involved on adenosine metabolism, such as 5′-nucleotidase and adenosine deaminase, were found to be reduced after RSV treatment, but adenosine levels remained unchanged. Nevertheless, an age-related decrease on 5′-nucleotidase activity and adenosine and related metabolite levels was observed. In conclusion, our data show that RSV modulates adenosine-mediated signalling, strongly suggesting that the role of RSV via adenosine receptor signalling and its modulation of neurotransmission in neurodegenerative diseases should be considered as new therapeutic target for RSV neuroprotective effect.


Resveratrol Adenosine signalling Aging Alzheimer’s disease SAMP8 mice 



This work has been supported by grants SAF2016-33307 from Ministerio de Economía y Competitividad to Mercè Pallas and PEII-2014-030-P from Junta de Comunidades de Castilla-La Mancha (JCCM) to Mairena Martín. Alejandro Sánchez-Melgar is the recipient of a postdoctoral fellowship (PRE-8002/2014) from JCCM.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1281_MOESM1_ESM.pdf (60 kb)
Supplemental Figure 1 Analysis of correlations within adenosinergic system in 5 months old mice. Components previously analyzed belonging to the adenosinergic system were correlated by using Pearson correlation as described in Methods. r. Pearson’s correlation coefficient. P. P value. Straight line: linear regression fit of Pearson’s correlation coefficient value. (PDF 60 kb)
12035_2018_1281_MOESM2_ESM.pdf (63 kb)
Supplemental Figure 2 Analysis of correlations within adenosinergic system in 7 months old mice. Components previously analyzed belonging to the adenosinergic system were correlated by using Pearson correlation as described in Methods. r. Pearson’s correlation coefficient. P. P value. Straight line: linear regression fit of Pearson’s correlation coefficient value. (PDF 63 kb)


  1. 1.
    Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53(4):527–552PubMedGoogle Scholar
  2. 2.
    Alonso-Andres P, Albasanz JL, Ferrer I, Martin M (2018) Purine-related metabolites and their converting enzymes are altered in frontal, parietal and temporal cortex at early stages of Alzheimer's disease pathology. Brain Pathol. CrossRefGoogle Scholar
  3. 3.
    Borea PA, Gessi S, Merighi S, Varani K (2016) Adenosine as a multi-signalling Guardian angel in human diseases: when, where and how does it exert its protective effects? Trends Pharmacol Sci 37(6):419–434. CrossRefPubMedGoogle Scholar
  4. 4.
    Antonioli L, Blandizzi C, Csoka B, Pacher P, Hasko G (2015) Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11(4):228–241. CrossRefPubMedGoogle Scholar
  5. 5.
    Ribeiro JA, Sebastiao AM, de Mendonca A (2002) Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol 68(6):377–392CrossRefGoogle Scholar
  6. 6.
    Cunha RA (2016) How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem 139:1019–1055. CrossRefPubMedGoogle Scholar
  7. 7.
    Albasanz JL, Perez S, Barrachina M, Ferrer I, Martin M (2008) Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease. Brain Pathol 18(2):211–219. CrossRefPubMedGoogle Scholar
  8. 8.
    Villar-Menendez I, Porta S, Buira SP, Pereira-Veiga T, Diaz-Sanchez S, Albasanz JL, Ferrer I, Martin M et al (2014) Increased striatal adenosine A2A receptor levels is an early event in Parkinson's disease-related pathology and it is potentially regulated by miR-34b. Neurobiol Dis 69:206–214. CrossRefPubMedGoogle Scholar
  9. 9.
    Villar-Menendez I, Blanch M, Tyebji S, Pereira-Veiga T, Albasanz JL, Martin M, Ferrer I, Perez-Navarro E et al (2013) Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington's disease. NeuroMolecular Med 15(2):295–309. CrossRefPubMedGoogle Scholar
  10. 10.
    Albasanz JL, Rodriguez A, Ferrer I, Martin M (2006) Adenosine A2A receptors are up-regulated in Pick's disease frontal cortex. Brain Pathol 16(4):249–255. CrossRefPubMedGoogle Scholar
  11. 11.
    Albasanz JL, Rodriguez A, Ferrer I, Martin M (2007) Up-regulation of adenosine A1 receptors in frontal cortex from Pick's disease cases. Eur J Neurosci 26(12):3501–3508. CrossRefPubMedGoogle Scholar
  12. 12.
    Castillo CA, Albasanz JL, Leon D, Jordan J, Pallas M, Camins A, Martin M (2009) Age-related expression of adenosine receptors in brain from the senescence-accelerated mouse. Exp Gerontol 44(6–7):453–461. CrossRefPubMedGoogle Scholar
  13. 13.
    Wei X, Zhang Y, Zhou J (1999) Alzheimer's disease-related gene expression in the brain of senescence accelerated mouse. Neurosci Lett 268(3):139–142CrossRefGoogle Scholar
  14. 14.
    Angulo E, Casado V, Mallol J, Canela EI, Vinals F, Ferrer I, Lluis C, Franco R (2003) A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain Pathol 13(4):440–451CrossRefGoogle Scholar
  15. 15.
    Fukumitsu N, Ishii K, Kimura Y, Oda K, Hashimoto M, Suzuki M, Ishiwata K (2008) Adenosine A(1) receptors using 8-dicyclopropylmethyl-1-[(11)C]methyl-3-propylxanthine PET in Alzheimer's disease. Ann Nucl Med 22(10):841–847. CrossRefPubMedGoogle Scholar
  16. 16.
    Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, Guo W, Kang J et al (2015) Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory. Nat Neurosci 18(3):423–434. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5(6):493–506. CrossRefPubMedGoogle Scholar
  18. 18.
    Syarifah-Noratiqah S, Naina-Mohamed I, Zulfarina MS, Qodriyah HM (2017) Natural polyphenols in the treatment of Alzheimer's disease. Curr Drug Targets 19:927–937. CrossRefGoogle Scholar
  19. 19.
    Bhandari R, Kuhad A (2017) Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int 103:8–23. CrossRefPubMedGoogle Scholar
  20. 20.
    Cianciulli A, Dragone T, Calvello R, Porro C, Trotta T, Lofrumento DD, Panaro MA (2015) IL-10 plays a pivotal role in anti-inflammatory effects of resveratrol in activated microglia cells. Int Immunopharmacol 24(2):369–376. CrossRefPubMedGoogle Scholar
  21. 21.
    Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS (2017) Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J Neuroinflammation 14(1):1. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ge L, Liu L, Liu H, Liu S, Xue H, Wang X, Yuan L, Wang Z et al (2015) Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice. Eur J Pharmacol 768:49–57. CrossRefPubMedGoogle Scholar
  23. 23.
    Rangarajan P, Karthikeyan A, Dheen ST (2016) Role of dietary phenols in mitigating microglia-mediated neuroinflammation. NeuroMolecular Med 18(3):453–464. CrossRefPubMedGoogle Scholar
  24. 24.
    Palomera-Avalos V, Grinan-Ferre C, Izquierdo V, Camins A, Sanfeliu C, Pallas M (2017) Metabolic stress induces cognitive disturbances and inflammation in aged mice: protective role of resveratrol. Rejuvenation Res 20(3):202–217. CrossRefPubMedGoogle Scholar
  25. 25.
    Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem 280(45):37377–37382. CrossRefPubMedGoogle Scholar
  26. 26.
    Jia Y, Wang N, Liu X (2017) Resveratrol and amyloid-beta: mechanistic insights. Nutrients 9(10). CrossRefGoogle Scholar
  27. 27.
    Gehm BD, McAndrews JM, Chien PY, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94(25):14138–14143CrossRefGoogle Scholar
  28. 28.
    El-Mowafy AM, Alkhalaf M (2003) Resveratrol activates adenylyl-cyclase in human breast cancer cells: a novel, estrogen receptor-independent cytostatic mechanism. Carcinogenesis 24(5):869–873CrossRefGoogle Scholar
  29. 29.
    Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H et al (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148(3):421–433. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tillu DV, Melemedjian OK, Asiedu MN, Qu N, De Felice M, Dussor G, Price TJ (2012) Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain. Mol Pain 8:5. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Razali N, Agarwal R, Agarwal P, Kumar S, Tripathy M, Vasudevan S, Crowston JG, Ismail NM (2015) Role of adenosine receptors in resveratrol-induced intraocular pressure lowering in rats with steroid-induced ocular hypertension. Clin Exp Ophthalmol 43(1):54–66. CrossRefPubMedGoogle Scholar
  32. 32.
    Gupta YK, Chaudhary G, Srivastava AK (2002) Protective effect of resveratrol against pentylenetetrazole-induced seizures and its modulation by an adenosinergic system. Pharmacology 65(3):170–174CrossRefGoogle Scholar
  33. 33.
    Leon D, Albasanz JL, Ruiz MA, Fernandez M, Martin M (2002) Adenosine A1 receptor down-regulation in mothers and fetal brain after caffeine and theophylline treatments to pregnant rats. J Neurochem 82(3):625–634CrossRefGoogle Scholar
  34. 34.
    Giust D, Da Ros T, Martin M, Albasanz JL (2014) [60]fullerene derivative modulates adenosine and metabotropic glutamate receptors gene expression: a possible protective effect against hypoxia. J Nanobiotechnol 12:27. CrossRefGoogle Scholar
  35. 35.
    Leon DA, Castillo CA, Albasanz JL, Martin M (2009) Reduced expression and desensitization of adenosine A1 receptor/adenylyl cyclase pathway after chronic (−)N6-phenylisopropyladenosine intake during pregnancy. Neuroscience 163(2):524–532. CrossRefPubMedGoogle Scholar
  36. 36.
    Leon-Navarro DA, Albasanz JL, Martin M (2015) Hyperthermia-induced seizures alter adenosine A1 and A2A receptors and 5′-nucleotidase activity in rat cerebral cortex. J Neurochem 134(3):395–404. CrossRefPubMedGoogle Scholar
  37. 37.
    Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F, Consortium R (2011) Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One 6(1):e16581. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang R, Zhang Y, Li J, Zhang C (2017) Resveratrol ameliorates spatial learning memory impairment induced by Abeta1-42 in rats. Neuroscience 344:39–47. CrossRefPubMedGoogle Scholar
  39. 39.
    Akiguchi I, Pallas M, Budka H, Akiyama H, Ueno M, Han J, Yagi H, Nishikawa T et al (2017) SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions. Neuropathology 37(4):293–305. CrossRefPubMedGoogle Scholar
  40. 40.
    Cheng J, Rui Y, Qin L, Xu J, Han S, Yuan L, Yin X, Wan Z (2017) Vitamin D combined with resveratrol prevents cognitive decline in SAMP8 mice. Curr Alzheimer Res 14(8):820–833. CrossRefPubMedGoogle Scholar
  41. 41.
    Porquet D, Casadesus G, Bayod S, Vicente A, Canudas AM, Vilaplana J, Pelegri C, Sanfeliu C et al (2013) Dietary resveratrol prevents Alzheimer's markers and increases life span in SAMP8. Age (Dordr) 35(5):1851–1865. CrossRefGoogle Scholar
  42. 42.
    Grinan-Ferre C, Palomera-Avalos V, Puigoriol-Illamola D, Camins A, Porquet D, Pla V, Aguado F, Pallas M (2016) Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence. Exp Gerontol 80:57–69. CrossRefPubMedGoogle Scholar
  43. 43.
    Mazzanti G, Di Giacomo S (2016) Curcumin and resveratrol in the management of cognitive disorders: what is the clinical evidence? Molecules 21(9). doi: CrossRefGoogle Scholar
  44. 44.
    Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA et al (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85(16):1383–1391. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Palomera-Avalos V, Grinan-Ferre C, Puigoriol-Ilamola D, Camins A, Sanfeliu C, Canudas AM, Pallas M (2017) Resveratrol protects SAMP8 brain under metabolic stress: focus on mitochondrial function and Wnt pathway. Mol Neurobiol 54(3):1661–1676. CrossRefPubMedGoogle Scholar
  46. 46.
    Folbergrova J, Jesina P, Kubova H, Otahal J (2018) Effect of resveratrol on oxidative stress and mitochondrial dysfunction in immature brain during epileptogenesis. Mol Neurobiol. CrossRefGoogle Scholar
  47. 47.
    Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC, de Oliveira MR (2017) Resveratrol and brain mitochondria: a review. Mol Neurobiol 55:2085–2101. CrossRefPubMedGoogle Scholar
  48. 48.
    Rui Y, Cheng J, Qin L, Shan C, Chang J, Wang G, Wan Z (2017) Effects of vitamin D and resveratrol on metabolic associated markers in liver and adipose tissue from SAMP8 mice. Exp Gerontol 93:16–28. CrossRefPubMedGoogle Scholar
  49. 49.
    Andre DM, Calixto MC, Sollon C, Alexandre EC, Leiria LO, Tobar N, Anhe GF, Antunes E (2016) Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice. Int Immunopharmacol 38:298–305. CrossRefPubMedGoogle Scholar
  50. 50.
    Fischer-Posovszky P, Kukulus V, Tews D, Unterkircher T, Debatin KM, Fulda S, Wabitsch M (2010) Resveratrol regulates human adipocyte number and function in a Sirt1-dependent manner. Am J Clin Nutr 92(1):5–15. CrossRefPubMedGoogle Scholar
  51. 51.
    Burnstock G, Gentile D (2018) The involvement of purinergic signalling in obesity. Purinergic Signal 14(2):97–108. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Milton-Laskibar I, Gomez-Zorita S, Aguirre L, Fernandez-Quintela A, Gonzalez M, Portillo MP (2017) Resveratrol-induced effects on body fat differ depending on feeding conditions. Molecules 22(12). CrossRefGoogle Scholar
  53. 53.
    Fernandez-Quintela A, Carpene C, Fernandez M, Aguirre L, Milton-Laskibar I, Contreras J, Portillo MP (2016) Anti-obesity effects of resveratrol: comparison between animal models and humans. J Physiol Biochem 73(3):417–429. CrossRefPubMedGoogle Scholar
  54. 54.
    Lange KW, Li S (2018) Resveratrol, pterostilbene, and dementia. Biofactors 44(1):83–90. CrossRefPubMedGoogle Scholar
  55. 55.
    Chiang MC, Nicol CJ, Cheng YC (2017) Resveratrol activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced inflammation and oxidative stress. Neurochem Int 115:1–10. CrossRefPubMedGoogle Scholar
  56. 56.
    Molino S, Dossena M, Buonocore D, Ferrari F, Venturini L, Ricevuti G, Verri M (2016) Polyphenols in dementia: from molecular basis to clinical trials. Life Sci 161:69–77. CrossRefPubMedGoogle Scholar
  57. 57.
    Liu Y, Beyer A, Aebersold R (2016) On the dependency of cellular protein levels on mRNA abundance. Cell 165(3):535–550. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Polycarpou E, Meira LB, Carrington S, Tyrrell E, Modjtahedi H, Carew MA (2013) Resveratrol 3-O-D-glucuronide and resveratrol 4'-O-D-glucuronide inhibit colon cancer cell growth: evidence for a role of A3 adenosine receptors, cyclin D1 depletion, and G1 cell cycle arrest. Mol Nutr Food Res 57(10):1708–1717. CrossRefPubMedGoogle Scholar
  59. 59.
    Mishina M, Kimura Y, Sakata M, Ishii K, Oda K, Toyohara J, Kimura K, Ishiwata K (2017) Age-related decrease in male extra-striatal adenosine A1 receptors measured using(11)C-MPDX PET. Front Pharmacol 8:903. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ekonomou A, Pagonopoulou O, Angelatou F (2000) Age-dependent changes in adenosine A1 receptor and uptake site binding in the mouse brain: an autoradiographic study. J Neurosci Res 60(2):257–265.<257::AID-JNR15>3.0.CO;2-U CrossRefPubMedGoogle Scholar
  61. 61.
    Meerlo P, Roman V, Farkas E, Keijser JN, Nyakas C, Luiten PG (2004) Ageing-related decline in adenosine A1 receptor binding in the rat brain: an autoradiographic study. J Neurosci Res 78(5):742–748. CrossRefPubMedGoogle Scholar
  62. 62.
    Stockwell J, Jakova E, Cayabyab FS (2017) Adenosine A1 and A2A receptors in the brain: current research and their role in neurodegeneration. Molecules 22(4). doi:
  63. 63.
    Snyder DL, Wang W, Pelleg A, Friedman E, Horwitz J, Roberts J (1998) Effect of aging on A1-adenosine receptor-mediated inhibition of norepinephrine release in the rat heart. J Cardiovasc Pharmacol 31(3):352–358CrossRefGoogle Scholar
  64. 64.
    Ashton KJ, Nilsson U, Willems L, Holmgren K, Headrick JP (2003) Effects of aging and ischemia on adenosine receptor transcription in mouse myocardium. Biochem Biophys Res Commun 312(2):367–372CrossRefGoogle Scholar
  65. 65.
    Garcia-Esparcia P, Hernandez-Ortega K, Ansoleaga B, Carmona M, Ferrer I (2015) Purine metabolism gene deregulation in Parkinson's disease. Neuropathol Appl Neurobiol 41(7):926–940. CrossRefPubMedGoogle Scholar
  66. 66.
    Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Goncalves N, Gorlewicz A, Malezieux M et al (2016) Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors. Nat Commun 7:11915. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Li P, Rial D, Canas PM, Yoo JH, Li W, Zhou X, Wang Y, van Westen GJ et al (2015) Optogenetic activation of intracellular adenosine A2A receptor signaling in the hippocampus is sufficient to trigger CREB phosphorylation and impair memory. Mol Psychiatry 20(11):1339–1349. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Kolahdouzan M, Hamadeh MJ (2017) The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neurosci Ther 23(4):272–290. CrossRefPubMedGoogle Scholar
  69. 69.
    Arendash GW, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J et al (2009) Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice. J Alzheimers Dis 17(3):661–680. CrossRefPubMedGoogle Scholar
  70. 70.
    Cunha RA (2005) Neuroprotection by adenosine in the brain: from a(1) receptor activation to a (2A) receptor blockade. Purinergic Signal 1(2):111–134. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Canas PM, Porciuncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, Oliveira CR, Cunha RA (2009) Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29(47):14741–14751. CrossRefPubMedGoogle Scholar
  72. 72.
    Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J (2006) Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience 142(4):941–952. CrossRefPubMedGoogle Scholar
  73. 73.
    Madeira MH, Elvas F, Boia R, Goncalves FQ, Cunha RA, Ambrosio AF, Santiago AR (2015) Adenosine A2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure. J Neuroinflammation 12:115. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Rebola N, Simoes AP, Canas PM, Tome AR, Andrade GM, Barry CE, Agostinho PM, Lynch MA et al (2011) Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. J Neurochem 117(1):100–111. CrossRefPubMedGoogle Scholar
  75. 75.
    Santiago AR, Baptista FI, Santos PF, Cristovao G, Ambrosio AF, Cunha RA, Gomes CA (2014) Role of microglia adenosine a(2A) receptors in retinal and brain neurodegenerative diseases. Mediat Inflamm 2014:465694–465613. CrossRefGoogle Scholar
  76. 76.
    Voloshyna I, Hai O, Littlefield MJ, Carsons S, Reiss AB (2013) Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARgamma and adenosine. Eur J Pharmacol 698(1–3):299–309. CrossRefPubMedGoogle Scholar
  77. 77.
    Guixa-Gonzalez R, Albasanz JL, Rodriguez-Espigares I, Pastor M, Sanz F, Marti-Solano M, Manna M, Martinez-Seara H et al (2017) Membrane cholesterol access into a G-protein-coupled receptor. Nat Commun 8:14505. CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Albasanz JL, Dalfo E, Ferrer I, Martin M (2005) Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes. Neurobiol Dis 20(3):685–693. CrossRefPubMedGoogle Scholar
  79. 79.
    Dalfo E, Albasanz JL, Rodriguez A, Martin M, Ferrer I (2005) Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in pick disease. J Neuropathol Exp Neurol 64(7):638–647CrossRefGoogle Scholar
  80. 80.
    Rodriguez-Perdigon M, Tordera RM, Gil-Bea FJ, Gerenu G, Ramirez MJ, Solas M (2016) Down-regulation of glutamatergic terminals (VGLUT1) driven by Abeta in Alzheimer's disease. Hippocampus 26(10):1303–1312. CrossRefPubMedGoogle Scholar
  81. 81.
    Holmes C, Smith H, Ganderton R, Arranz M, Collier D, Powell J, Lovestone S (2001) Psychosis and aggression in Alzheimer's disease: the effect of dopamine receptor gene variation. J Neurol Neurosurg Psychiatry 71(6):777–779CrossRefGoogle Scholar
  82. 82.
    Seeman P (2010) Dopamine D2 receptors as treatment targets in schizophrenia. Clin Schizophr Relat Psychoses 4(1):56–73. CrossRefPubMedGoogle Scholar
  83. 83.
    Gardoni F, Di Luca M (2006) New targets for pharmacological intervention in the glutamatergic synapse. Eur J Pharmacol 545(1):2–10. CrossRefPubMedGoogle Scholar
  84. 84.
    de Almeida LM, Pineiro CC, Leite MC, Brolese G, Tramontina F, Feoli AM, Gottfried C, Goncalves CA (2007) Resveratrol increases glutamate uptake, glutathione content, and S100B secretion in cortical astrocyte cultures. Cell Mol Neurobiol 27(5):661–668. CrossRefPubMedGoogle Scholar
  85. 85.
    Li Z, You Z, Li M, Pang L, Cheng J, Wang L (2017) Protective effect of resveratrol on the brain in a rat model of epilepsy. Neurosci Bull 33(3):273–280. CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Ethemoglu MS, Seker FB, Akkaya H, Kilic E, Aslan I, Erdogan CS, Yilmaz B (2017) Anticonvulsant activity of resveratrol-loaded liposomes in vivo. Neuroscience 357:12–19. CrossRefPubMedGoogle Scholar
  87. 87.
    Pallas M, Ortuno-Sahagun D, Benito-Andres P, Ponce-Regalado MD, Rojas-Mayorquin AE (2014) Resveratrol in epilepsy: preventive or treatment opportunities? Front Biosci (Landmark Ed) 19:1057–1064CrossRefGoogle Scholar
  88. 88.
    Ruiz MA, Leon DA, Albasanz JL, Martin M (2011) Desensitization of adenosine a(1) receptors in rat immature cortical neurons. Eur J Pharmacol 670(2–3):365–371. CrossRefPubMedGoogle Scholar
  89. 89.
    Ruiz MA, Albasanz JL, Leon D, Ros M, Andres A, Martin M (2005) Different modulation of inhibitory and stimulatory pathways mediated by adenosine after chronic in vivo agonist exposure. Brain Res 1031(2):211–221. CrossRefPubMedGoogle Scholar
  90. 90.
    Chen JF (2014) Adenosine receptor control of cognition in normal and disease. Int Rev Neurobiol 119:257–307. CrossRefPubMedGoogle Scholar
  91. 91.
    Schmatz R, Schetinger MR, Spanevello RM, Mazzanti CM, Stefanello N, Maldonado PA, Gutierres J, Correa Mde C et al (2009) Effects of resveratrol on nucleotide degrading enzymes in streptozotocin-induced diabetic rats. Life Sci 84(11–12):345–350. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Inorganic and Organic Chemistry and Biochemistry, Faculty of Chemical Sciences and Technologies, Faculty of Medicine of Ciudad Real, Regional Center of Biomedical Research (CRIB)University of Castilla-La Mancha (UCLM)Ciudad RealSpain
  2. 2.Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of NeuroscienceUniversity of BarcelonaBarcelonaSpain

Personalised recommendations