Guanosine Prevents Anhedonic-Like Behavior and Impairment in Hippocampal Glutamate Transport Following Amyloid-β1-40Administration in Mice.
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). Aβ1-40or 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. Aβ1-40increased 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. Aβ1-40induced an increase in hippocampal ADP levels. Aβ1-40decreased 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 Aβ1-40that seem to be linked to glutamate transport unbalance and alterations on purine and metabolite levels in mouse hippocampus.
Post-Graduation Program in Neuroscience, Federal University of Santa Catarina, Florianópolis, Brazil.|Departament of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil.
Débora
D
Lanznaster
Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Brazil.
Josiel M
JM
Mack
Departament of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil.
Victor
V
Coelho
Departament of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Neurobiology Department, Max Plank Institute for Biophysical Chemistry, Göttingen, Germany.
Marcelo
M
Ganzella
Departament of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Roberto F
RF
Almeida
Post-Graduation Program in Neuroscience, Federal University of Santa Catarina, Florianópolis, Brazil.|Departament of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil.
Tharine
T
Dal-Cim
Departament of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Gisele
G
Hansel
Departament of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
Eduardo R
ER
Zimmer
Departament of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Diogo O
DO
Souza
Post-Graduation Program in Neuroscience, Federal University of Santa Catarina, Florianópolis, Brazil.|Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Brazil.
Rui D
RD
Prediger
Post-Graduation Program in Neuroscience, Federal University of Santa Catarina, Florianópolis, Brazil. carla.tasca@ufsc.br.|Departament of Biochemistry, Federal University of Santa Catarina, Florianópolis, Brazil. carla.tasca@ufsc.br.
Carla I
CI
Tasca
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D006151:Guanosine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology
D027322:Amino Acid Transport System X-AG; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D006151:Guanosine; D018698:Glutamic Acid
Alzheimer’s disease; Anhedonia; Aβ1–40; Glutamate transport; Guanosine; Learning and memory