Anticonvulsant and Antiepileptogenic Effects Mediated by Adeno-Associated Virus Vector Neuropeptide Y Expression in the Rat Hippocampus

Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and k...

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Bibliographic Details
Published in:The Journal of neuroscience 2004-03, Vol.24 (12), p.3051-3059
Main Authors: Richichi, Cristina, Lin, En-Ju D, Stefanin, Daniela, Colella, Daniele, Ravizza, Teresa, Grignaschi, Giuliano, Veglianese, Pietro, Sperk, Gunther, During, Matthew J, Vezzani, Annamaria
Format: Article
Language:English
Subjects:
Animals
Dependovirus - genetics
Disease Models, Animal
Electroencephalography - drug effects
Epilepsy - physiopathology
Epilepsy - prevention & control
Epilepsy - therapy
Gene Expression
Gene Transfer Techniques
Genetic Therapy - methods
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Hippocampus - drug effects
Hippocampus - metabolism
Hippocampus - physiopathology
Injections, Intraventricular
Kainic Acid
Kindling, Neurologic
Male
Neurobiology of Disease
Neuropeptide Y - biosynthesis
Neuropeptide Y - genetics
Neuropeptide Y - therapeutic use
Rats
Rats, Sprague-Dawley
Seizures - chemically induced
Seizures - physiopathology
Seizures - prevention & control
Treatment Outcome
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Summary:Neuropeptide Y (NPY) inhibits seizures in experimental models and reduces excitability in human epileptic tissue. We studied the effect of long-lasting NPY overexpression in the rat hippocampus with local application of recombinant adeno-associated viral (AAV) vectors on acute kainate seizures and kindling epileptogenesis. Transgene expression was significantly increased by 7 d, reached maximal expression by 2 weeks, and persisted for at least 3 months. Serotype 2 AAV vector increased NPY expression in hilar interneurons, whereas the chimeric serotype 1/2 vector caused far more widespread expression, also including mossy fibers, pyramidal cells, and the subiculum. EEG seizures induced by intrahippocampal kainate were reduced by 50-75%, depending on the vector serotype, and seizure onset was markedly delayed. In rats injected with the chimeric serotype 1/2 vector, status epilepticus was abolished, and kindling acquisition was significantly delayed. Thus, targeted NPY gene transfer provides a potential therapeutic principle for the treatment of drug-resistant partial epilepsies.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.4056-03.2004