Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures.
Gene therapy using recombinant adeno-associated viral vectors overexpressing neuropeptide Y in the hippocampus exerts seizure-suppressant effects in rodent epilepsy models and is currently considered for clinical application in patients with intractable mesial temporal lobe epilepsy. Seizure suppression by neuropeptide Y in the hippocampus is predominantly mediated by Y2 receptors, which, together with neuropeptide Y, are upregulated after seizures as a compensatory mechanism. To explore whether such upregulation could prevent seizures, we overexpressed Y2 receptors in the hippocampus using recombinant adeno-associated viral vectors. In two temporal lobe epilepsy models, electrical kindling and kainate-induced seizures, vector-based transduction of Y2 receptor complementary DNA in the hippocampus of adult rats exerted seizure-suppressant effects. Simultaneous overexpression of Y2 and neuropeptide Y had a more pronounced seizure-suppressant effect. These results demonstrate that overexpression of Y2 receptors (alone or in combination with neuropeptide Y) could be an alternative strategy for epilepsy treatment.
Woldbye
David P D
DP
Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden.
Angehagen
Mikael
M
Gøtzsche
Casper R
CR
Elbrønd-Bek
Heidi
H
Sørensen
Andreas T
AT
Christiansen
Søren H
SH
Olesen
Mikkel V
MV
Nikitidou
Litsa
L
Hansen
Thomas V O
TV
Kanter-Schlifke
Irene
I
Kokaia
Merab
M
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006624:Hippocampus / Q000378:metabolism*; D007608:Kainic Acid / Q000009:adverse effects; D007696:Kindling, Neurologic / Q000235:genetics / Q000502:physiology; D008297:Male; D011485:Protein Binding / Q000235:genetics; D011859:Radiography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D012640:Seizures / Q000209:etiology / Q000473:pathology* / Q000628:therapy*; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014158:Transcription, Genetic / Q000502:physiology
D017476:Receptors, Neuropeptide Y; D013460:Sulfur Isotopes; C095889:neuropeptide Y2 receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D007608:Kainic Acid