title: Caffeine and an adenosine A(2A) receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life.
abstract: Seizures early in life cause long-term behavioral modifications, namely long-term memory deficits in experimental animals. Since caffeine and adenosine A(2A) receptor (A(2A)R) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long-term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7-days-old (P7) rats caused a single period of self-extinguishable convulsions which lead to a poorer memory performance in the Y-maze only when rats were older than 90 days, without modification of locomotion or anxiety-like behavior in the elevated-plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP-25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD-95, NMDA receptor subunits (NR1, NR2A, NR2B) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A(2A)R antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A(2A)R antagonists.
authors.affiliation: Center for Neurosciences of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Giana P
authors.initials: GP
authors.lastname: Cognato
authors.forename: Paula M
authors.initials: PM
authors.lastname: Agostinho
authors.forename: Jörg
authors.initials: J
authors.lastname: Hockemeyer
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
authors.forename: Diogo O
authors.initials: DO
authors.lastname: Souza
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007608:Kainic Acid; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000150:complications; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D005904:Glial Fibrillary Acidic Protein; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D011743:Pyrimidines; D050765:Qa-SNARE Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C494210:Snap25 protein, rat; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D014230:Triazoles; D014970:Xanthines; D014316:Tritium; C111599:istradefylline; D002110:Caffeine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D007608:Kainic Acid