biie-0246 and Memory-Disorders

Memory is the ability to store, retrieve and use information that requires a progressive time-dependent stabilization process known as consolidation to be established. The hippocampus is essential for processing all the information that forms memory, especially spatial memory. Neuropeptide Y (NPY) affects memory, so in this study we investigated the participation and recruitment of NPY receptors during spatial memory consolidation in rats. Using the water maze test, we show that NPY (1 pmol) injected into the dorsal hippocampus impaired memory consolidation and that previous restraint stress (30 min) potentiates NPY effects, i.e. further impaired memory consolidation. Using selective antagonists for NPY Y

Topics: Animals; Arginine; Behavior, Animal; Benzazepines; Disease Models, Animal; Male; Memory Disorders; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Restraint, Physical; Spatial Memory; Stress, Psychological

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 μmol/μL) 15 min prior to the i.c.v. injection of aggregated Aβ1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aβ1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aβ1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aβ1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aβ1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aβ1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aβ1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.

Topics: Amyloid beta-Peptides; Animals; Arginine; Benzazepines; Cerebral Cortex; Depression; Glutathione; Glutathione Peroxidase; Hippocampus; Injections, Intraventricular; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Mice; Motor Activity; Neuropeptide Y; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Receptors, Neuropeptide Y

Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment.

Topics: Animals; Arginine; Benzazepines; Dependovirus; Discrimination, Psychological; Excitatory Postsynaptic Potentials; Genetic Therapy; Genetic Vectors; Hippocampus; Injections; Long-Term Potentiation; Male; Memory Disorders; Neuronal Plasticity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Recombinant Fusion Proteins; Transduction, Genetic; Transgenes