Abstract
Amyloid-beta (Aβ) peptides are the major neuropathological hallmarks related with Alzheimer’s disease (AD). Aβ peptides trigger several biochemical mechanisms of neurotoxicity, including neuroinflammation and glutamatergic neurotransmission impairment. Guanosine is the endogenous guanine-derived nucleoside that modulates the glutamatergic system and the cellular redox status, thus acting as a neuroprotective agent. Here, we investigated the putative neuroprotective effect of guanosine in an AD-like mouse model. Adult mice received a single intracerebroventricular injection of Aβ1–40 (400 pmol/site) or vehicle and then were treated immediately, 3 h later, and once a day during the subsequent 14 days with guanosine (8 mg/kg, intraperitoneally). Aβ1–40 or guanosine did not alter mouse locomotor activity and anxiety-related behaviors. Aβ1–40-treated mice displayed short-term memory deficit in the object location task that was prevented by guanosine. Guanosine prevented the Aβ1–40-induced increase in latency to grooming in the splash test, an indicative of anhedonia. Aβ1–40 increased Na+-independent glutamate uptake in ex vivo hippocampal slices, and guanosine reversed it to control levels. The repeated administration of guanosine increased hippocampal GDP levels, which was not observed in the group treated with Aβ plus guanosine. Aβ1–40 induced an increase in hippocampal ADP levels. Aβ1–40 decreased GFAP expression in the hippocampal CA1 region, an effect not modified by guanosine. No differences were observed concerning synaptophysin and NeuN immunolabeling. Together, these results show that guanosine prevents memory deficit and anhedonic-like behavior induced by Aβ1–40 that seem to be linked to glutamate transport unbalance and alterations on purine and metabolite levels in mouse hippocampus.
Similar content being viewed by others
References
Mazurek AA (2000) Treatment of Alzheimer’s disease. N Engl J Med 342(11):821 author reply 821-822
Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. doi:10.1038/nrd3505
Masters CL, Selkoe DJ (2012) Biochemistry of amyloid beta-protein and amyloid deposits in Alzheimer disease. Cold Spring Harbor Perspect Med 2(6):a006262. doi:10.1101/cshperspect.a006262
Selkoe DJ (2001) Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis: JAD 3(1):75–80
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185
Parameshwaran K, Dhanasekaran M, Suppiramaniam V (2008) Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 210(1):7–13. doi:10.1016/j.expneurol.2007.10.008
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875. doi:10.1523/JNEUROSCI.4970-06.2007
Figueiredo CP, Bicca MA, Latini A, Prediger RD, Medeiros R, Calixto JB (2011) Folic acid plus alpha-tocopherol mitigates amyloid-beta-induced neurotoxicity through modulation of mitochondrial complexes activity. J Alzheimers Dis: JAD 24(1):61–75. doi:10.3233/JAD-2010-101320
Martins WC, dos Santos VV, dos Santos AA, Vandresen-Filho S, Dal-Cim TA, de Oliveira KA, Mendes-de-Aguiar CB, Farina M, Prediger RD, Viola GG, Tasca CI (2015) Atorvastatin prevents cognitive deficits induced by intracerebroventricular amyloid-beta1–40 administration in mice: involvement of glutamatergic and antioxidant systems. Neurotox Res 28(1):32–42. doi:10.1007/s12640-015-9527-y
Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, Campos MM, Calixto JB (2007) Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer’s disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci 27(20):5394–5404. doi:10.1523/JNEUROSCI.5047-06.2007
Piermartiri TCB, Figueiredo CP, Rial D, Duarte FS, Bezerra SC, Mancini G, de Bem AF, Prediger RDS, Tasca CI (2010) Atorvastatin prevents hippocampal cell death, neuroinflammation and oxidative stress following amyloid-β1–40 administration in mice: evidence for dissociation between cognitive deficits and neuronal damage. Exp Neurol 226:274–284. doi:10.1016/j.expneurol.2010.08.030
Prediger RD, Franco JL, Pandolfo P, Medeiros R, Duarte FS, Di Giunta G, Figueiredo CP, Farina M, Calixto JB, Takahashi RN, Dafre AL (2007) Differential susceptibility following beta-amyloid peptide-(1-40) administration in C57BL/6 and Swiss albino mice: evidence for a dissociation between cognitive deficits and the glutathione system response. Behav Brain Res 177(2):205–213. doi:10.1016/j.bbr.2006.11.032
Pamplona FA, Pandolfo P, Duarte FS, Takahashi RN, Prediger RDS (2010) Altered emotionality leads to increased pain tolerance in amyloid beta (a beta 1-40) peptide-treated mice. Behav Brain Res 212(1):96–102. doi:10.1016/j.bbr.2010.03.052
Ledo JH, Azevedo EP, Clarke JR, Ribeiro FC, Figueiredo CP, Foguel D, De Felice FG, Ferreira ST (2013) Amyloid-beta oligomers link depressive-like behavior and cognitive deficits in mice. Mol Psychiatry 18(10):1053–1054. doi:10.1038/mp.2012.168
Modrego PJ, Ferrandez J (2004) Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol 61(8):1290–1293. doi:10.1001/archneur.61.8.1290
Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MM (2008) History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70(15):1258–1264. doi:10.1212/01.wnl.0000308937.30473.d1
Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62(1):63–77. doi:10.1016/j.neuropharm.2011.07.036
Tokita K, Yamaji T, Hashimoto K (2012) Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol Biochem Behav 100(4):688–704. doi:10.1016/j.pbb.2011.04.016
de Oliveira J, Moreira EL, Mancini G, Hort MA, Latini A, Ribeiro-do-Valle RM, Farina M, da Rocha JB, de Bem AF (2013) Diphenyl diselenide prevents cortico-cerebral mitochondrial dysfunction and oxidative stress induced by hypercholesterolemia in LDL receptor knockout mice. Neurochem Res 38(10):2028–2036. doi:10.1007/s11064-013-1110-4
Schmidt AP, Avila TT, Souza DO (2005) Intracerebroventricular guanine-based purines protect against seizures induced by quinolinic acid in mice. Neurochem Res 30(1):69–73
Schmidt AP, Lara DR, de Faria MJ, da Silveira PA, Onofre Souza D (2000) Guanosine and GMP prevent seizures induced by quinolinic acid in mice. Brain Res 864:40–43. doi:10.1016/S0006-8993(00)02106-5
Tavares RG, Schmidt AP, Abud J, Tasca CI, Souza DO (2005) In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine. Neurochem Res 30:439–444
Tavares RG, Schmidt AP, Tasca CI, Souza DO (2008) Quinolinic acid-induced seizures stimulate glutamate uptake into synaptic vesicles from rat brain: effects prevented by guanine-based purines. Neurochem Res 33(1):97–102. doi:10.1007/s11064-007-9421-y
Dal-Cim T, Martins WC, Santos AR, Tasca CI (2011) Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca(2)+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake. Neuroscience 183:212–220. doi:10.1016/j.neuroscience.2011.03.022
Dal-Cim T, Martins WC, Thomaz DT, Coelho V, Poluceno GG, Lanznaster D, Vandresen-Filho S, Tasca CI (2016) Neuroprotection promoted by guanosine depends on glutamine synthetase and glutamate transporters activity in hippocampal slices subjected to oxygen/glucose deprivation. Neurotox Res. doi:10.1007/s12640-015-9595-z
Quincozes-Santos A, Bobermin LD, de Souza DG, Bellaver B, Gonçalves CA, Souza DO (2013) Gliopreventive effects of guanosine against glucose deprivation in vitro. Purinergic Signal 9:643–654. doi:10.1007/s11302-013-9377-0
Almeida RF, Comasseto DD, Ramos DB, Hansel G, Zimmer ER, Loureiro SO, Ganzella M, Souza DO (2016) Guanosine anxiolytic-like effect involves adenosinergic and glutamatergic neurotransmitter systems. Mol Neurobiol. doi:10.1007/s12035-015-9660-x
Molz S, Dal-Cim T, Budni J, Martin-de-Saavedra MD, Egea J, Romero A, del Barrio L, Rodrigues AL, Lopez MG, Tasca CI (2011) Neuroprotective effect of guanosine against glutamate-induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol-3 kinase/Akt/ glycogen synthase kinase 3beta pathway activation and inducible nitric oxide synthase inhibition. J Neurosci Res 89(9):1400–1408. doi:10.1002/jnr.22681
Deutschenbaur L, Beck J, Kiyhankhadiv A, Muhlhauser M, Borgwardt S, Walter M, Hasler G, Sollberger D, Lang UE (2016) Role of calcium, glutamate and NMDA in major depression and therapeutic application. Prog Neuro-Psychopharmacol Biol Psychiatry 64:325–333. doi:10.1016/j.pnpbp.2015.02.015
Bettio LE, Cunha MP, Budni J, Pazini FL, Oliveira A, Colla AR, Rodrigues AL (2012) Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways. Behav Brain Res 234(2):137–148. doi:10.1016/j.bbr.2012.06.021
Pettifer KM, Kleywegt S, Bau CJ, Ramsbottom JD, Vertes E, Ciccarelli R, Caciagli F, Werstiuk ES, Rathbone MP (2004) Guanosine protects SH-SY5Y cells against beta-amyloid-induced apoptosis. Neuroreport 15(5):833–836
Tarozzi A, Merlicco A, Morroni F, Bolondi C, Di Iorio P, Ciccarelli R, Romano S, Giuliani P, Hrelia P (2010) Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by amyloid-beta peptide oligomers. J Biol Regul Homeost Agents 24(3):297–306
ElKhoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382(6593):716–719
Rial D, Castro AA, Machado N, Garcao P, Goncalves FQ, Silva HB, Tome AR, Kofalvi A, Corti O, Raisman-Vozari R, Cunha RA, Prediger RD (2014) Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson’s disease. PLoS One 9(12):e114216. doi:10.1371/journal.pone.0114216
Assini FL, Duzzioni M, Takahashi RN (2009) Object location memory in mice: pharmacological validation and further evidence of hippocampal CA1 participation. Behav Brain Res 204(1):206–211. doi:10.1016/j.bbr.2009.06.005
Onaolapo OJ, Onaolapo AY, Mosaku TJ, Akanji OO, Abiodun OR (2012) Elevated plus maze and Y-maze behavioral effects of subchronic, oral low dose monosodium glutamate in Swiss albino mice. J Pharm Biol Sci 3(4):21–27
Isingrini E, Camus V, Le Guisquet AM, Pingaud M, Devers S, Belzung C (2010) Association between repeated unpredictable chronic mild stress (UCMS) procedures with a high fat diet: a model of fluoxetine resistance in mice. PLoS One 5(4):e10404. doi:10.1371/journal.pone.0010404
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85(3):367–370
Ludka FK, Zomkowski AD, Cunha MP, Dal-Cim T, Zeni AL, Rodrigues AL, Tasca CI (2013) Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels. Eur Neuropsychopharmacol 23(5):400–412. doi:10.1016/j.euroneuro.2012.05.005
Molz S, Decker H, Oliveira IJ, Souza DO, Tasca CI (2005) Neurotoxicity induced by glutamate in glucose-deprived rat hippocampal slices is prevented by GMP. Neurochem Res 30(1):83–89
Molz S, Tharine DC, Decker H, Tasca CI (2008) GMP prevents excitotoxicity mediated by NMDA receptor activation but not by reversal activity of glutamate transporters in rat hippocampal slices. Brain Res 1231:113–120. doi:10.1016/j.brainres.2008.07.009
Schmidt AP, Bohmer AE, Leke R, Schallenberger C, Antunes C, Pereira MS, Wofchuk ST, Elisabetsky E, Souza DO (2008) Antinociceptive effects of intracerebroventricular administration of guanine-based purines in mice: evidences for the mechanism of action. Brain Res 1234:50–58. doi:10.1016/j.brainres.2008.07.091
Schmidt AP, Tort AB, Silveira PP, Bohmer AE, Hansel G, Knorr L, Schallenberger C, Dalmaz C, Elisabetsky E, Crestana RH, Lara DR, Souza DO (2009) The NMDA antagonist MK-801 induces hyperalgesia and increases CSF excitatory amino acids in rats: reversal by guanosine. Pharmacol Biochem Behav 91(4):549–553. doi:10.1016/j.pbb.2008.09.009
Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622. doi:10.1373/clinchem.2008.112797
Muller AP, Gnoatto J, Moreira JD, Zimmer ER, Haas CB, Lulhier F, Perry ML, Souza DO, Torres-Aleman I, Portela LV (2011) Exercise increases insulin signaling in the hippocampus: physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice. Hippocampus 21(10):1082–1092. doi:10.1002/hipo.20822
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275
Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83(2):346–356
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, S-i O, Dziewczapolski G, Nakamura T, Cao G, Pratt aE, Kang Y-J, Tu S, Molokanova E, McKercher SR, Hires S, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts a, Tong G, Fang-Newmeyer T, Parker J, Holland E, Zhang D, Nakanishi N, Chen H-SV, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Pina-Crespo JC, Lipton S (2013) A induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci 110:E2518–E2527. doi:10.1073/pnas.1306832110
Lanznaster D, Dal-Cim T, Piermartiri TC, Tasca CI (2016) Guanosine: a neuromodulator with therapeutic potential in aging-related disorders. Aging Dis 7(5). doi:10.14336/AD.2016.0208
Paniz LG, Calcagnotto ME, Pandolfo P, Machado DG, Santos GF, Hansel G, Almeida RF, Bruch RS, Brum LM, Torres FV, de Assis AM, Rico EP, Souza DO (2014) Neuroprotective effects of guanosine administration on behavioral, brain activity, neurochemical and redox parameters in a rat model of chronic hepatic encephalopathy. Metab Brain Dis 29(3):645–654. doi:10.1007/s11011-014-9548-x
Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9(7):532–544. doi:10.1038/nrn2420
Matheus FC, Rial D, Real JI, Lemos C, Ben J, Guaita GO, Pita IR, Sequeira AC, Pereira FC, Walz R, Takahashi RN, Bertoglio LJ, Cunha CD, Cunha RA, Prediger RD (2016) Decreased synaptic plasticity in the medial prefrontal cortex underlies short-term memory deficits in 6-OHDA-lesioned rats. Behav Brain Res 301:43–54. doi:10.1016/j.bbr.2015.12.011
Garabadu D, Ahmad A, Krishnamurthy S (2015) Risperidone attenuates modified stress-Re-stress paradigm-induced mitochondrial dysfunction and apoptosis in rats exhibiting post-traumatic stress disorder-like symptoms. J Mol Neurosci: MN 56(2):299–312. doi:10.1007/s12031-015-0532-7
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93(3):358–364
Bettio LE, Freitas AE, Neis VB, Santos DB, Ribeiro CM, Rosa PB, Farina M, Rodrigues AL (2014) Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress. Pharmacol Biochem Behav 127:7–14. doi:10.1016/j.pbb.2014.10.002
Bender AS, Reichelt W, Norenberg MD (2000) Characterization of cystine uptake in cultured astrocytes. Neurochem Int 37(2–3):269–276
Bringmann A, Pannicke T, Biedermann B, Francke M, Iandiev I, Grosche J, Wiedemann P, Albrecht J, Reichenbach A (2009) Role of retinal glial cells in neurotransmitter uptake and metabolism. Neurochem Int 54(3–4):143–160. doi:10.1016/j.neuint.2008.10.014
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Qin S, Colin C, Hinners I, Gervais A, Cheret C, Mallat M (2006) System xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta peptide 1-40. J Neurosci 26(12):3345–3356. doi:10.1523/JNEUROSCI.5186-05.2006
Albrecht P, Henke N, Tien ML, Issberner A, Bouchachia I, Maher P, Lewerenz J, Methner A (2013) Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity. Neurochem Int 62(5):610–619. doi:10.1016/j.neuint.2013.01.019
Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58(4):495–505. doi:10.1002/ana.20624
Giuliani P, Ballerini P, Ciccarelli R, Buccella S, Romano S, D’Alimonte I, Poli A, Beraudi A, Pena E, Jiang S, Rathbone MP, Caciagli F, Di Iorio P (2012) Tissue distribution and metabolism of guanosine in rats following intraperitoneal injection. J Biol Regul Homeost Agents 26(1):51–65
Bicca MA, Figueiredo CP, Piermartiri TC, Meotti FC, Bouzon ZL, Tasca CI, Medeiros R, Calixto JB (2011) The selective and competitive N-methyl-D-aspartate receptor antagonist, (−)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid, prevents synaptic toxicity induced by amyloid-beta in mice. Neuroscience 192:631–641. doi:10.1016/j.neuroscience.2011.06.038
Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58(7):831–838. doi:10.1002/glia.20967
Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. doi:10.1016/j.neulet.2013.12.071
Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14(11):1225–1236
Cobb JA, O’Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL, Miguel-Hidalgo J, Rajkowska G, Stockmeier CA (2015) Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience. doi:10.1016/j.neuroscience.2015.12.044
Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10(2):509–519
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8(8):1051–1058. doi:10.1038/nn1503
Zahs KR, Ashe KH (2010) ‘Too much good news’—are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends Neurosci 33(8):381–389. doi:10.1016/j.tins.2010.05.004
Acknowledgments
Research was supported by grants from the Brazilian funding agencies, CAPES (PVE 052/2012), CNPq (INCT for Excitotoxicity and Neuroprotection), and FAPESC (NENASC/PRONEX) to C.I.T. C.I.T. is recipient of CNPq productivity fellowship. D.L. was recipient of CAPES/PVE 052/2012 and CAPES/Procad predoctoral scholarships. D.L. kindly thanks Prof. Dra. Zenilda Bouzon (UFSC) for helping with the acquisition of images presented in Fig. 1.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Lanznaster, D., Mack, J.M., Coelho, V. et al. Guanosine Prevents Anhedonic-Like Behavior and Impairment in Hippocampal Glutamate Transport Following Amyloid-β1–40 Administration in Mice. Mol Neurobiol 54, 5482–5496 (2017). https://doi.org/10.1007/s12035-016-0082-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-016-0082-1