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 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.
Richichi
Cristina
C
Department of Neuroscience, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy.
Lin
En-Ju D
EJ
Stefanin
Daniela
D
Colella
Daniele
D
Ravizza
Teresa
T
Grignaschi
Giuliano
G
Veglianese
Pietro
P
Sperk
Günther
G
During
Matthew J
MJ
Vezzani
Annamaria
A
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007276:Injections, Intraventricular; D007608:Kainic Acid; D007696:Kindling, Neurologic; D008297:Male; D009478:Neuropeptide Y / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D016896:Treatment Outcome
D009478:Neuropeptide Y; D007608:Kainic Acid